TW201706263A - Compounds - Google Patents

Abstract

Compounds of formula (I): wherein X, Y, R1 and R3-R11 are as herein defined, and salts thereof are PAD4 inhibitors and may be useful in the treatment of various disorders, for example rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosis, and psoriasis.

Description

Compound

The present invention relates to certain compounds which are inhibitors of PAD4, to processes for their preparation, to pharmaceutical compositions comprising such compounds, and to the use of such compounds or compositions in the treatment of various conditions. Compounds that inhibit PAD4 are useful in the treatment of various conditions such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis.

PAD4 is a member of the peptidyl arginine deamidase (PAD) family of enzymes that catalyze the acidification of arginine to citrulline in the peptide sequence. PAD4 is responsible for the de-imidization or citrulliation of various proteins in vitro and in vivo, and the results of different functional responses in various diseases ( Jones JE et al., Curr. Opin. Drug Discov. Devel., 12(5), (2009), 616-627 ). Examples of exemplary diseases include rheumatoid arthritis, diseases that contribute to pathogenic neutrophils (eg, vasculitis, systemic lupus erythematosus, ulcerative colitis), and tumor complications. PAD4 inhibitors can also be more widely used in human diseases via epigenetic mechanisms as tools and therapeutic agents.

Inhibitors of PAD4 may have utility for rheumatoid arthritis (RA). RA affects autoimmune diseases in approximately 1% of the population (Wegner N. et al., Immunol. Rev., 233(1) (2010), 34-54) . It is characterized by inflammation of the joints that cause debilitating destruction of bone and cartilage. A weak genetic association between PAD4 polymorphism and RA susceptibility has been demonstrated in multiple population studies, albeit inconsistent (eg, Kochi Y. et al., Ann. Rheum. Dis., 70, (2011), 512- 515 ). PAD4 (and family member PAD2) has been detected in synovial tissue and is responsible for the deimination of various conjugating proteins. It is speculated that this process results in disruption of tolerance to citrullinated receptors (eg, fibrinogen, vimentin, and collagen) in the RA joint and the initiation of an immune response to the host. These anti-citrullinated protein antibodies (ACPA) promote disease pathogenicity and can also be used as a diagnostic test for RA (eg, commercially available CCP2 or cyclic citrullinated protein 2 test). In addition, increased citrulline may also provide an additional direct contribution to disease pathogenicity via its ability to directly affect the function of several joints and inflammatory mediators (eg, fibrinogen, antithrombin, multiple chemokines). In a smaller subgroup of RA patients, anti-PAD4 antibodies can be measured and associated with more aggressive forms of disease (Darrah E et al, Sci Transl Med. May 22, 2013; 5 (186)) .

PAD4 inhibitors can also be used to reduce pathological neutrophil activity in a variety of diseases. Studies have shown that the process of neutrophil extracellular trapping (NET) formation (an innate defense mechanism by which neutrophils can fix and kill pathogens) is associated with tissue protein citrulline and in PAD4 knockout mice. Lack of ( Neeli I. et al., J. Immunol., 180, (2008), 1895-1902 and Li P. et al., J. Exp. Med., 207(9), (2010), 1853-1862 ) . Therefore, the PAD4 inhibitor can be applied to NET in tissues to form diseases that promote local damage and disease pathology. Such diseases include, but are not limited to, small vessel vasculitis ( Kessenbrock K. et al, Nat. Med., 15 (6), (2009), 623-625; Ohlsson SM et al, Clin Exp Immunol. 2014 Jun; 176(3): 363-72) , systemic lupus erythematosus ( Hakkim A. et al., Proc. Natl. Acad. Sci. USA, 107 (21), (2010), 9813-9818 and Villanueva E. et al. J. Immunol., 187(1), (2011), 538-52), ulcerative colitis (Savchenko A. et al., Pathol. Int., 61(5), (2011), 290-7) , pouch Sexual fibrosis ( Dwyer M et al, J Innate Immun. 2014; 6(6): 765-79 ), asthma (Dworski R. et al., J. Allergy Clin. Immunol., 127(5), (2011), 1260-6;) , deep vein thrombosis (Fuchs T. et al, Proc. Natl. Acad. Sci. USA, 107 (36), (2010), 15880-5) , root periostitis (Vitkov L. et al. Human, Ultrastructural Pathol., 34(1), (2010), 25-30) , sepsis (Clark SR et al, Nat. Med., 13(4), (2007), 463-9) , appendicitis (Brinkmann V Et al, Science, 303, (2004), 1532-5) , type 2 diabetes and stroke. In addition, there is evidence that NET can cause diseases that affect the skin, such as cutaneous lupus erythematosus ( Villanueva E. et al., J. Immunol., 187(1), (2011), 538-52) and psoriasis ( Lin AM et al. The pathology in J. Immunol., 187(1), (2011), 490-500 ), therefore, the PAD4 inhibitor may exhibit the benefit of treating NET skin disorders when administered by systemic or dermal routes. PAD4 inhibitors can affect additional functions in the neutrophil and are more widely applicable to neutrophil diseases.

Studies have demonstrated the efficacy of a tool for PAD inhibitors (such as chlor- quinone ) in animal models of multiple diseases, including collagen-induced arthritis ( Willis V. C. et al., J. Immunol., 186(7), (2011), 4396-4404 ), experimental colitis induced by sodium dextran sulfate (DSS) ( Chumanevich AA et al, Am. J. Physiol. Gastrointest. Liver Physiol., 300 (6), (2011), G929-G938 ), MRL/lpr mice susceptible to lupus, atherosclerosis and arterial thrombosis (Knight JS et al, Circ Res. 2014 Mar 14; 114(6): 947-56 ), spinal cord repair (Lange S. et al., Dev. Biol., 355(2), (2011), 205-14) and experimental autoimmune encephalomyelitis (EAE). DSS colitis reports also show that chlor-quinone drives apoptosis in inflammatory cells in vitro and in vivo, suggesting that PAD4 inhibitors are generally more effective in a wide range of inflammatory diseases.

PAD4 inhibitors are also useful in the treatment of cancer ( Slack. JL et al, Cell. Mol. Life Sci., 68(4), (2011), 709-720 ). Overexpression of PAD4 has been demonstrated in a variety of cancers ( Chang X. et al., BMC Cancer, 9, (2009), 40 ). According to the following observations, the anti-proliferative effect of PAD4 inhibitors has been demonstrated: in the promoter of p53-target genes (eg, p21, which is involved in the induction of cell cycle arrest and apoptosis), the PAD4 guanamined tissue protein Amino acid residues ( Li P. et al., Mol. Cell Biol., 28(15), (2008), 4745-4758 ).

The above-mentioned effects of PAD4 in the arginine residues in the deiminated tissue protein may indicate the general role of PAD4 in the regulation of gene expression. PAD4 is observed as a major member of the PAD family that resides in the nucleus as well as in the cytoplasm. The early evidence that PAD4 can be used as a tissue protein demethylimidozyme and a deiminase is inconsistent and unproven. However, it can indirectly reduce the tissue protein arginine methylation (and thus the subsequent regulation associated with this marker) by conversion to citrulline via depletion of available arginine residues. Thus, PAD4 inhibitors can be used as an epigenetic tool or therapeutic to influence the performance of target genes in additional disease settings. PAD4 inhibitors also effectively control the degree of citrulline and the conversion of pluripotency and differentiation in stem cells ( Christophorou MA et al, Nature. March 6, 2014; 507 (7490): 104-8 ), and therefore, therapeutic A pluripotent state and differentiation potential affecting different stem cells including, but not limited to, embryonic stem cells, neural stem cells, hematopoietic stem cells, and cancer stem cells.

The present invention relates to a compound of formula (I),

Wherein X, Y, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ and R ₁₁ are as defined below; and salts thereof.

Certain compounds of the invention have been shown to be PAD4 inhibitors and may also exhibit enhanced selectivity for PAD4 relative to PAD2. For example, certain compounds of the invention indicate 100-fold selectivity for inhibition of PAD4 relative to PAD2 inhibition. Compounds that inhibit PAD4 are useful in the treatment of various conditions such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis. Accordingly, the invention further relates to a compound comprising formula (I) or a pharmaceutically acceptable compound thereof Salt pharmaceutical composition. The invention still further relates to a method of treating a condition associated therewith using a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The invention is further directed to a process for the preparation of the compounds of the invention.

In a first aspect, a compound of formula (I) is provided:

And a salt thereof; wherein: X is O or S; Y is N or CR ₂ R ₁ is -H or -C _1-6 alkyl; R ₂ is -H, -OH, -C _1-6 alkyl, - OC _1-6 alkyl, -CN, -halo, -C(=O)NH ₂ , -C _1-6 haloalkyl, -OC _1-6 alkyl-OC _1-6 alkyl, -OC _{1 -6-} alkyl-OH, -OC _1-6 alkyl-C(=O)NH ₂ , -OC _1-6 alkyl-CN, -OC _1-6 haloalkyl, -NH-C _1-6 alkane , -N(C _1-6 alkyl) ₂ or heteroaryl; R ₃ -C _1-6 alkyl, -C _1-6 alkyl-NH ₂ or -C _1-6 alkyl-OC _{1 -6} alkyl; R ₄ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-heteroaryl (wherein the heteroaryl is optionally used, 2 or 3 C _1-6 alkyl-substituted), -C _1-6 alkyl-phenyl (wherein the phenyl group is optionally substituted by 1, 2 or 3 substituents selected from the list consisting of : halo, C _1-6 alkyl and -OC _1-6 alkyl), -C _1-6 alkyl-heterocyclyl, -C _1-6 alkyl-C _3-6 cycloalkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-CN or -C _1-6 alkyl-OC _1-6 alkyl; R ₅ -H, -C _1-6 alkyl, -OC _{1 -6} alkyl, -OH, -halo or -CN; or R ₄ together with R ₅ is -(R ₄ )-CH ₂ CH ₂ O-(R ₅ )-, -(R ₄ )-CH ₂ CH ₂ CH ₂ O-(R ₅ )- or -(R ₄ )-CH(Me)CH ₂ O-(R ₅ )-, wherein -(R ₄ )- and -(R ₅ )- represents the position at which the alkenyloxy chain is attached to each ring atom; R ₆ is -H, -halo, -CN, -C _1-6 alkyl, -OC _{1 -6} alkyl or -OH; R ₇ is -H, -halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₈ -H, -F or - C _1-6 alkyl; R ₉ -H or -C _1-6 alkyl; and R ₁₀ is -H and R ₁₁ is a 5 to 7 membered monocyclic saturated heterocyclic ring (containing 1 nitrogen atom and optionally 1) An oxygen atom) or a 7-membered bicyclic heterocyclic ring (containing 1 nitrogen atom) or -CH ₂ CH ₂ NH ₂ ; or NR ₁₀ R ₁₁ together form a 5- to 7-membered monocyclic or bicyclic saturated salt containing 1 nitrogen atom Or an unsaturated heterocyclic ring wherein the heterocyclic ring is substituted by 1, 2 or 3 substituents independently selected from the list consisting of: -NH ₂ , -C _1-6 alkyl-NH ₂ , -NH- C _1-6 alkyl, -NHC(=NH)CH ₂ Cl, -C _1-6 alkyl, -halo, -OC _1-6 alkyl, -OH and -C(O)NH ₂ .

In one embodiment, a compound of formula (I) is provided:

And a salt thereof; wherein: X is O or S; Y is N or CR ₂ R ₁ is -H or -C _1-6 alkyl; R ₂ is -H, -OH, -C _1-6 alkyl, - OC _1-6 alkyl, -CN, -halo, -C(=O)NH ₂ , -C _1-6 haloalkyl, -OC _1-6 alkyl-OC _1-6 alkyl, -OC _{1 -6-} alkyl-OH, -OC _1-6 alkyl-C(=O)NH ₂ , -OC _1-6 alkyl-CN, -OC _1-6 haloalkyl, -NH-C _1-6 alkane , -N(C _1-6 alkyl) ₂ or heteroaryl; R ₃ -C _1-6 alkyl, -C _1-6 alkyl-NH ₂ or -C _1-6 alkyl-OC _{1 -6} alkyl; R ₄ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-heteroaryl (wherein the heteroaryl is optionally used, 2 or 3 C _1-6 alkyl-substituted), -C _1-6 alkyl-phenyl (wherein the phenyl group is optionally substituted by 1, 2 or 3 substituents selected from the list consisting of : halo, C _1-6 alkyl and -OC _1-6 alkyl), -C _1-6 alkyl-heterocyclyl, -C _1-6 alkyl-C _3-6 cycloalkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-CN or -C _1-6 alkyl-OC _1-6 alkyl; R ₅ -H, -C _1-6 alkyl, -OC _{1 -6} alkyl, -OH, -halo or -CN; or R ₄ together with R ₅ is -(R ₄ )-CH ₂ CH ₂ O-(R ₅ )-, -(R ₄ )-CH ₂ CH ₂ CH ₂ O-(R ₅ )- or -(R ₄ )-CH(Me)CH ₂ O-(R ₅ )-, wherein -( R ₄ )- and -(R ₅ )- represent the position at which the alkenyloxy chain is attached to each ring atom; R ₆ is -H, -halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₇ is -H, -halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₈ -H, -F or -C _1-6 alkyl; R ₉ -H or -C _1-6 alkyl; and R ₁₀ is -H and R ₁₁ is a 5 to 7 membered monocyclic saturated heterocyclic ring containing one nitrogen atom and optionally 1 oxygen atom) or 7-membered bicyclic heterocyclic ring (containing 1 nitrogen atom) or -CH ₂ CH ₂ NH ₂ ; or NR ₁₀ R ₁₁ together form a 5- to 7-membered monocyclic or bicyclic ring containing 1 nitrogen atom a saturated or unsaturated heterocyclic ring wherein the heterocyclic ring is substituted by 1, 2 or 3 substituents independently selected from the list consisting of: -NH ₂ , -C _1-6 alkyl-NH ₂ , -NH -C _1-6 alkyl, -NHC(=NH)CH ₂ Cl, -C _1-6 alkyl, -halo, -OC _1-6 alkyl, -OH and -C(O)NH ₂ ; The compound of formula (I) is not (3-aminohexahydropyridin-1-yl)(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[ d]imidazol-5-yl)methanone, ((3S,4R)-3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-) Ind-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) Ketone or (R)-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazol-5-yl)methanone.

In one embodiment, a compound of formula (I) is provided:

And a salt thereof; wherein: X is O or S; Y is N or CR ₂ R ₁ is -H or -C _1-6 alkyl; R ₂ is -H, -OH, -C _1-6 alkyl, - OC _1-6 alkyl, -CN, -halo, -C(=O)NH ₂ , -C _1-6 haloalkyl, -OC _1-6 alkyl-OC _1-6 alkyl, -OC _{1 -6-} alkyl-OH, -OC _1-6 alkyl-C(=O)NH ₂ , -OC _1-6 alkyl-CN, -OC _1-6 haloalkyl, -NH-C _1-6 alkane , -N(C _1-6 alkyl) ₂ or heteroaryl; R ₃ -C _2-6 alkyl, -C _1-6 alkyl-NH ₂ , or -C _1-6 alkyl-OC _1-6 alkyl; R ₄ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-heteroaryl (wherein the heteroaryl is optionally 1 , 2 or 3 C _1-6 alkyl substituted), -C _1-6 alkyl-phenyl (wherein the phenyl group optionally consists of 1, 2 or 3 substituents selected from the list consisting of Substituents: halo, C _1-6 alkyl and -OC _1-6 alkyl), -C _1-6 alkyl-heterocyclyl, -C _1-6 alkyl-C _3-6 cycloalkyl, - C _1-6 alkyl-OH, -C _1-6 alkyl-CN or -C _1-6 alkyl-OC _1-6 alkyl; R ₅ -H, -C _1-6 alkyl, -OC _1-6 alkyl, -OH, -halo or -CN; or R ₄ together with R ₅ is -(R ₄ )-CH ₂ CH ₂ O-(R ₅ )-, -(R ₄ )-CH _{2 CH 2 CH 2 O- (R 5} ) - or _{- (R 4) -CH (Me} ) CH 2 O- (R 5) -, which - (R ₄₎ - and - (R ₅₎ - represents a chain alkenyl group attached to the respective position of the ring atoms; R ₆ based -H, - halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₇ -H, -halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₈ -H, - F or -C _1-6 alkyl; R ₉ -H or -C _1-6 alkyl; and R ₁₀ is -H and R ₁₁ is a 5 to 7 membered monocyclic saturated heterocyclic ring (containing 1 nitrogen atom and Depending on the case of one oxygen atom) or a 7-membered bicyclic heterocycle (containing 1 nitrogen atom) or -CH ₂ CH ₂ NH ₂ ; or NR ₁₀ R ₁₁ together form a 5 to 7 membered monocyclic ring containing 1 nitrogen atom or a bicyclic saturated or unsaturated heterocyclic ring wherein the heterocyclic ring is substituted by 1, 2 or 3 substituents independently selected from the list consisting of: -NH ₂ , -C _1-6 alkyl-NH ₂ , -NH-C _1-6 alkyl, -NHC(=NH)CH ₂ Cl, -C _1-6 alkyl, -halo, -OC _1-6 alkyl, -OH and -C(O)NH ₂ .

In one embodiment, X is O.

In one embodiment, the X system is S.

In one embodiment, Y is N.

In one embodiment, Y is CR ₂ .

In one embodiment, R ₁ is -H or -methyl.

In one embodiment, R ₁ is -H.

In one embodiment, R ₂ is -H, -O-Me, -O-CF ₃ , -CN, -Br, -CF ₃ , - 3-pyridyl, -C(=O)NH ₂ , -NMe ₂ , -NHMe, ethyl, methyl, -O-CH ₂ CH ₂ CH ₂ -OH, -O-Et, -O-CH ₂ CH ₂ -O-CH ₃ , -O-CH ₂ CH ₂ -OH , -OCH ₂ CN, -O-CH ₂ C(O)NH ₂ or -OH.

In one embodiment, R ₂ is -H or -OC _1-6 alkyl.

In one embodiment, R ₂ is -H or -O-Me.

In one embodiment, R ₃ is -methyl, -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ CH ₂ NH ₂ , -ethyl, -CH ₂ CH ₂ OCH ₃ or -isopropyl.

In one embodiment, R ₃ is -C _1-6 alkyl.

In one embodiment, R ₃ is -methyl.

In one embodiment, R ₄ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-heteroaryl (optionally substituted with 1 methyl), -C _1-6 alkyl-phenyl (optionally substituted by 1 or 2 substituents independently selected from the list consisting of: Cl, I, -Me and -OMe), -C _1-6 alkyl -heterocyclyl, -C _1-6 alkyl-C _3-6 cycloalkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-CN or -C _1-6 alkyl-OC _1-6 alkyl;

In one embodiment, R ₄ is -H, methyl, ethyl, cyclopropylmethyl, -CH ₂ CN, 2,2,2-trifluoroethyl, isopropyl, 3-chlorobenzyl, 3-pyridylmethyl, 4-methylbenzyl, -isobutyl, (1-methyl-1H-pyrazol-4-yl)methyl, -CH ₂ CH ₂ OCH ₃ , benzyl, 4- Iodobenzyl, 2-pyridylmethyl, hydroxyethyl, 4-chlorobenzyl, (R) -3-hydroxy-2-methylpropan-1-yl, 3,4-dichlorobenzyl, 4- Methoxybenzyl, tetrahydro-2H-piperidin-4-ylmethyl, -CH ₂ CH ₂ CH ₂ OCH ₃ or (S)-3-hydroxy-2-methylpropan-1-yl.

In one embodiment, R ₄ is -C _1-6 alkyl-C _3-6 cycloalkyl, -C _1-6 haloalkyl, -C _1-6 alkyl, -C _1-6 alkyl- Heteroaryl (optionally substituted by 1 methyl) or -C _1-6 alkyl-phenyl.

In one embodiment, R ₄ is cyclopropylmethyl, 2,2,2-trifluoroethyl, benzyl, 3-pyridylmethyl or (1-methyl-1H-pyrazol-4-yl) ) methyl or ethyl.

In one embodiment, R ₅ is -H, -O-Me, -methyl, -ethyl, -Br, -OH, -F or -CN.

In one embodiment, R ₅ is -H.

In one embodiment, R ₄ together with R ₅ is -(R ₄ )-CH ₂ CH ₂ O-(R ₅ )-, -(R ₄ )-CH ₂ CH ₂ CH ₂ O-(R ₅ )- Or -(R ₄ )-CH(Me)CH ₂ O-(R ₅ )-.

In one embodiment, R ₆ is -H, -O-Me, -F, -CN, -Br, -methyl or -O-Et.

In one embodiment, R ₆ is -H.

In one embodiment, R ₇ is -H, -O-Me, -Cl, -F, -methyl, -CN or -OH.

In one embodiment, R ₇ is -H.

In one embodiment, R ₈ is -H, -methyl or -F.

In one embodiment, R ₈ is -H.

In one embodiment, R ₉ is -H or -ethyl.

In one embodiment, R ₉ is H.

In one embodiment, R ₁₀ is -H and R ₁₁ is azepan-3-yl, 1,4-oxazepan-3-yl, -CH ₂ CH ₂ NH ₂ or 3-aza Bicyclo[4.1.0]hept-1-yl.

In one embodiment, -NR ₁₀ R _{11 is} selected from the list consisting of hexahydropyridyl (optionally substituted by one or two substituents selected from the list consisting of: -NH ₂ , -NH-C _1-6 alkyl, -C _1-6 alkyl-NH ₂ , -OC _1-6 alkyl, -OH, -C _1-6 alkyl, -halo, -C(=O)NH ₂ and - NHC(=NH)CH ₂ Cl), dihydrohexahydropyridyl (optionally substituted by -NH ₂ ), azabicyclo[3.1.0]hexyl (optionally substituted by -NH ₂ ) and pyrrolidinyl ( Optionally, one or two substituents selected from the list consisting of: -NH ₂ , -C _1-6 alkyl, and -C _1-6 alkyl-NH ₂ ).

In one embodiment, -NR ₁₀ R _{11 is} selected from the list consisting of:

Where * indicates an attachment point to a carbonyl or thiocarbonyl residue

In one embodiment, the -NR ₁₀ R ₁₁ system or .

In one embodiment, the -NR ₁₀ R ₁₁ system .

In one embodiment, the compound of the invention is selected from the list consisting of: (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-({2-[1-ethyl-7-(methyloxy)-1 H -吲) Indole-2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-{[2-(3,4-di Hydrogen-2 H -[1,4]oxazepine[2,3,4- hi ]indole-6-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl} -3-hexahydropyridinium; (3 R )-1-{[2-(2,3-dihydro[1,4]oxazino[2,3,4- hi ]indole-5-yl) 1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-{[1-methyl-2-(3-methyl-2) ,3-dihydro[1,4]oxazino[2,3,4- hi ]indole-5-yl)-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinium (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-7-(methyloxy)-1 H -benzimidazole- 5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-({2-[1-(cyclopropylmethyl)-5-(methyloxy)-1 H -吲哚) -2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({2-[1-ethyl-6 - (methyloxy) -1 H - indol-2 ] -1-methyl -1 H - benzimidazol-5-yl} carbonyl) -3-hexahydro-pyridinamine; [2- (5 - {[ (3 R) -3- amino-1-hexahydro- Pyridyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1 H -indol-1-yl]acetonitrile; (3 R )-1-{[2-(1-B -6-fluoro-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1- ({1-Methyl-2-[1-(2,2,2-trifluoroethyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)- 3-hexahydropyridinium; (3 R )-1-({1-methyl-2-[1-(1-methylethyl)-1 H -indol-2-yl]-1 H -benzene And imidazol-5-yl}carbonyl)-3-hexahydropyridinium; 2-(5-{[(3 R )-3-amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1-ethyl-1 H -indole-6-carbonitrile; (3 R )-1-[(2-{1-[(3-chlorophenyl)) (1) H -indol-2-yl}-1-methyl-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; (3 R )-1-({1 -methyl-2-[1-(3-pyridylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({2-[1-(cyclopropylmethyl)-1 H -indol-2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)- 3-hexahydropyridinamine; (3 R )-1-[(1-methyl-2-{1- [(4-methylphenyl)methyl]-1 H -indol-2-yl}-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; (3 R )- 1-{[2-(1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1 -({1-Methyl-2-[1-(2-methylpropyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexa Hydropyridylamine; (3 R )-1-[(1-methyl-2-{1-[(1-methyl-1 H -pyrazol-4-yl)methyl]-1 H -吲哚- 2-yl}-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; (3 R )-1-{[2-(5-chloro-1-ethyl-1 H - Indole-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-[(1-methyl-2- {1-[2-(Methyloxy)ethyl]-1 H -indol-2-yl}-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; (3 R )-1-{[2-(6-bromo-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3 - hexahydropyridinium; (3 R )-1-({1-methyl-2-[1-(phenylmethyl)-1 H -indol-2-yl]-1 H -benzimidazole - 5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-[(2-{1-[(4-iodophenyl)methyl]-1 H -indol-2-yl} 1-methyl -1 H - benzimidazol-5-yl) carbonyl] -3-piperidine ; (3 R) -1 - { [2- (1- ethyl-6-methyl -1 H - indol-2-yl) -1-methyl -1 H - benzimidazol-5-yl] Carbonyl}-3-hexahydropyridinamine; (3 R )-1-({1-methyl-2-[1-(2-pyridylmethyl)-1H-indol-2-yl]-1H- Benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({1-methyl-2-[1-(4-pyridylmethyl)-1H-indole 2-yl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; 2-[2-(5-{[(3 R )-3-amino-1-hydrogen) Pyridyl]carbonyl}-1-methyl-1H-benzoimidazol-2-yl)-1H-indol-1-yl]ethanol; (3 R )-1-[(2-{1-[(4) -chlorophenyl)methyl]-1H-indol-2-yl}-1-methyl-1H-benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; ( R )-(3 -aminohexahydropyridin-1-yl)(2-(1-ethyl-6,7-dimethoxy-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazo-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(6-ethoxy-1-ethyl-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (( R )-3-aminohexahydropyridin-1-yl)(2-(1-((R))) -3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (R) - (3- amino-hexahydro-1-yl) (2- (1-ethyl -1H- Indol-2-yl) -1-methyl-7- (trifluoromethoxy) lH-benzo [d] imidazol-5-yl) methanone; (R) -5- (3- amino six Hydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-7-carbonitrile; ( R )-( 3-aminohexahydropyridin-1-yl)(7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 -yl)methanone; ( R) -(3-aminohexahydropyridin-1-yl)(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzene And [d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-(3,4-dichlorobenzyl)-1H-indole)哚-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1) -(4-methoxybenzyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; 1-({1-methyl -2-[1-(tetrahydro-2 H -pyran-4-ylmethyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3- Hexahydropyridinium; 1-{[2-(6-bromo-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl} -3-hexahydropyridinium; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl -1H-benzo[d]imidazol-5-yl)methanone; (3 R )-1-({1-methyl-2 -[1-(2,2,2-trifluoroethyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; ( R )-3-Aminohexahydropyridin-1-yl)(2-(1-((R)-3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7 -methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-( Cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3 -aminohexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl) -1H-benzo[d]imidazol-5-yl)methanone; (3 S )-1-({1-methyl-2-[1-(phenylmethyl)-1 H -吲哚-2 -yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; ( S )-(3-aminohexahydropyridin-1-yl)(1-methyl-2- (1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone; (1 R ,5 S )-3-{[2-(1-B -1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-azabicyclo[3.1.0]hexan-1-amine; R )-(1-(2-Aminoethyl)-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)(3-amine yl-hexahydro-1-yl) methanone; (R) - (3- amino-hexahydro-1-yl) (2- (1 LH-indol-2-yl) -1-methyl-7- (trifluoromethyl) lH-benzo [d] imidazol-5-yl) methanone; (+/-) - cis -(3-Amino-4-ethoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazolyl-5-yl)methanone; (+/-)-((cis)-3-amino-4-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H) -indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; cis- (3-amino-2-methylhexahydropyridin-1-yl (2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; cis- (5-amino group- 2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)A Ketone; N-(azepan-3-yl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-formamide; (3-aminopyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl- 1H-benzo[d]imidazol-5-yl)methanone; (3-aminocyclopentyl)(2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H -benzo[d]imidazol-5-yl)methanone; ((3 S ,4 R )-3-amino-4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl) Benzyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo [d]imidazol-5-yl)methanone; ((3 R ,4 S )-3-amino-4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl-2 -(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone; (3 R )-1- [(1-Methyl-2-{1-[(1-methyl-1 H -pyrazol-4-yl)methyl]-1 H -indol-2-yl}-1 H -benzimidazole -5-yl)carbonyl]-3-hexahydropyridinamine; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-5-fluoro-1H-indole- 2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-B) -1H-indol-2-yl)-1-methyl-7-(pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)methanone; ( R )-5-( 3-Aminopyrrolidine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-7-carboxamide ( R )-(3-Aminohexahydropyridin-1-yl)(7-(dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-yl -1H-benzo[d]imidazol-5-yl)methanone; 2-(1-ethyl-1H-indol-2-yl)-1-methyl-N-(1,4-oxonitrogen) Heterocyclic hept-6-yl)-1H-benzo[d]imidazol-5-carbamimid; ((3 S ,4 R )-3-amino-4-hydroxyhexahydropyridin-1-yl)( 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5-(yl)methanone; ((3 S ,4 R )-3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indole) -2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ((3 S ,4 R )-3-amino-4-hydroxyl Hexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-yl Ketone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(methyl Amino)-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(7-methoxy-2-(1-() 3-methoxypropyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-amino-6 Hydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-2-yl) -1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(7-methoxy-2-(1-(2-) Methoxyethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridine -1-yl)(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5 -yl)methanone; (( R )-3-aminohexahydropyridin-1-yl)(2-(1-(( S) )-3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone ( R )-2-(2-(5-(3-Aminohexahydropyridine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-2-yl -1H-indol-1-yl)acetonitrile; ( R )-(3-aminohexahydropyridin-1-yl)(7-ethyl-2-(1-ethyl-1H-indole-2) -yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; N- (azepan-3-yl)-2-(1-ethyl-1H-indole 2-yl) -1-methyl -1H- benzo [d] imidazole-5-acyl-amine; (S) - N - (azepan-3-yl) -2- (1-ethyl -1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carboxamide; ( R )-N-(1-(2-(1-benzyl-1H) -吲哚-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)-2-chloroacetamidine; ( R )-(3-amine (hexahydropyridin-1-yl)(2-(7-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-5,6-dimethoxy-1H-indol-2-yl)-1-methyl-1H -benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(3-ethyl-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; 1-{[2-(1-ethyl-7) -methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; N-(2-aminoethyl)- 1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazole-5-carboxamide; 1-{[2-(1-ethyl) -5-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; 1-{[2-(1- Ethyl-4-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; ( R )-2-( 5-(3-Aminohexahydropyridine-1-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)- 1-ethyl-1H-indole-5-carbonitrile; 2-(1-Ethyl-1 H -indol-2-yl)-1-methyl- N- (hexahydropyridin-3-yl)-1 H -benzo[ d ]imidazole-5-formamidine ( S )-(3-(Aminomethyl)pyrrolidin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H - Benzo[ d ]imidazol-5-yl)methanone; (2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazole-5 -yl)(3-(methylamino)hexahydropyridin-1-yl)methanone; N- (2-aminoethyl)-2-(1-ethyl-1 H -indole-2- -1-methyl-1 H -benzo[ d ]imidazol-5-carboxamide (3,4- cis )-1-{[2-(1-ethyl-1 H -吲哚- 2-yl)-1-methyl-1 H -benzimidazol-5-yl ]carbonyl}-3,4-hexahydropyridinediamine; (+/-)-((cis)-4-amino-2-methylpyrrolidin-1-yl)(2-(1-ethyl) -1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)( 2-(1-ethyl-1H-indol-2-yl)-1,7-dimethyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-amine Hexylhydropyridin-1-yl)(1-(3-aminopropyl)-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5- yl) methanone; (R) - (3- amino-hexahydro-1-yl) (1-ethyl-2- (1-ethyl-lH-indol-2-yl) lH-benzo [d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3- methyl-3H-imidazo[4,5-b]pyridin-6-yl)methanone; trans (+/-)-3-amino-4-fluorohexahydropyridin-1-yl)(2- (1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazol-5-yl)methanone; cis -((+/-)-3 -amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5- Methyl ketone; trans -((+/-)-3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone; cis (+/-)-3-amino-4- Methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazol-5-yl) Methyl ketone; (3 R )-1-{[2-(7-bromo-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl ]carbonyl}-3-hexahydropyridinamine; 2-(5-{[(3 R )-3-amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazole- 2-yl)-1-ethyl-1 H -indole-7-ol; 2-(5-{[(3 R )-3-amino-1-hexahydropyridinyl]carbonyl}-1- yl -1 H - benzimidazol-2-yl) -1- (cyclopropylmethyl) -1 H - indol-5-ol; 2- (5 - {[( 3 R) -3- amino 1-hexahydropyridyl]carbonyl}-1-methyl-1 H -benzoimidazol-2-yl)-1-ethyl-1 H -indole-6-ol; (3 R )-1- {[2-(1-Ethyl-7-fluoro-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinium ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-4-fluoro-1H-indol-2-yl)-1-methyl-1H-benzo [d]imidazol-5-yl)methanone; 2-(5-{[(3 R )-3-amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazole -2-yl)-1-ethyl-1 H -indole-7-carbonitrile; 5-amino-5,6-dihydropyridine-1(2 H )-yl)(2-(1-B) yl -1 H - indol-2-yl) -1-methyl -1 H - benzo [d] imidazole 5-yl) methanone; (R) - (3- amino-hexahydro-1-yl) (2- (1-ethyl -1H- indol-2-yl) -7- (3-hydroxy Propyl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(7-ethoxy- 2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydro) Pyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-(2-methoxyethoxy)-1-methyl-1H-benzo[d] Imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-(2- Hydroxyethoxy)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-2-((5-(3-aminohexahydropyridine-1-carbonyl)) -2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)oxy)acetonitrile; ( R )-2-(( 5-(3-Aminohexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-7- Ethyl)oxyacetamide; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1 -methyl-1H-benzo[d]imidazol-5-yl)methanone; (+/-)-(3-amino-4-methylhexahydropyridin-1-yl)(2-(1- Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl) One, a trans - isomer; trans-3-amino-4-methyl-piperidine-1-yl) (2- (1-ethyl -1H- indol-2-yl) -1- methyl-1H-benzo[d]imidazol-5-yl)methanone; (+/-)-(3-amino-4-methylhexahydropyridin-1-yl)(2-(1-B) -1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, cis- isomer; cis- 3-amino-4- Methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (+/-)- cis- 5-amino-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 -carbonyl) hexahydropyridine-3-carboxamide; (3-amino-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone; cis- (3-amino-5-methylhexahydropyridin-1-yl)(2-(1-ethyl) -1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; trans- (3-amino-5-methylhexahydropyridine-1 -yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (3-amino-5 -fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)- Ketone; (+/-)-((cis)-3,5-diamino-6 Pyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (+/- )-(( trans )-3-amino-5-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl- 1H-benzo[d]imidazol-5-yl)methanone; (3-amino-5-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (+/-)- cis- 3-amino-1-(2-(1-ethyl-1H-) Indole-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-4-carboxamide; (3-aminohexahydropyridin-1-yl) ( 1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydro) Pyridin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-1-(2-methoxyethyl)-1H-benzo[d]imidazol-5-yl) Methyl ketone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-1-isopropyl-1H-benzo[ d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-yl -1H-benzo[d]imidazol-5-yl)methanethione; ( cis -(+/-)-3-amino-4-fluorohexahydropyridin-1-yl)(2-(1) -ethyl-1 H -indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl Ketone; (+/-)-(2-(aminomethyl)hexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-yl yl -1 H - benzo [d] imidazol-5-yl) methanone; ((3 S, 4 R ) -3- amino-4-fluoro-piperidine-1-yl) (2- (1 Ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone; ((3 R ,4 S )-3-amino- 4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-1- Methyl-1H-benzo[d]imidazol-5-yl)methanone; N- (3-azabicyclo[4.1.0]hept-1-yl)-2-(1-ethyl-1H- Ind-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carboxamide; and (3-aminohexahydropyridin-1-yl)(2-(1-benzyl) -1 H -indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; and salts thereof.

In one embodiment, the compound of the invention is selected from the list consisting of: (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1- Methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinium hydrochloride (3 R )-1-({2-[1-ethyl-7-(methyloxy) -1 H -indol-2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-{[2- (3,4-Dihydro-2 H -[1,4]oxazepine[2,3,4- hi ]indole-6-yl)-1-methyl-1 H -benzimidazole- 5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-{[2-(2,3-dihydro[1,4]oxazino[2,3,4- hi ]吲哚-5-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-{[1-methyl-2-( 3-methyl-2,3-dihydro[1,4]oxazino[2,3,4- hi ]indol-5-yl)-1 H -benzimidazol-5-yl]carbonyl}- 3-hexahydropyridinium; (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-7-(methyloxy)-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1- methyl-7- (methyloxy) -1 H - benzene Imidazol-5-yl] carbonyl} -3-piperidine hydrochloride; (3 R) -1 - ( {2- [1- ( cyclopropylmethyl) -5- (methyloxy) - 1 H -indol-2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({2-[1 -ethyl-6-(methyloxy)-1 H -indol-2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; [2-(5-{[(3 R )-3-Amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1 H -吲哚-1-yl]acetonitrile; (3 R )-1-{[2-(1-ethyl-6-fluoro-1 H -indol-2-yl)-1-methyl-1 H -benzimidazole -5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-({1-methyl-2-[1-(2,2,2-trifluoroethyl)-1 H - Indole-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({1-methyl-2-[1-(1) -methylethyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; 2-(5-{[(3 R ) 3-amino-1-hexahydropyridyl]carbonyl}-1-methyl-1 H -benzoimidazol-2-yl)-1-ethyl-1 H -indole-6-carbonitrile; 3 R )-1-[(2-{1-[(3-chlorophenyl)methyl]-1 H -indol-2-yl}-1-methyl-1 H -benzimidazole-5- (carbonyl)-3-hexahydropyridinamine; (3 R )-1-({1- Methyl-2-[1-(3-pyridylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({2-[1-(cyclopropylmethyl)-1 H -indol-2-yl]-1-methyl-1 H -benzimidazol-5-yl}carbonyl)-3 - hexahydropyridinium; (3 R )-1-[(1-methyl-2-{1-[(4-methylphenyl)methyl]-1 H -indol-2-yl}-1 H -benzimidazol-5-yl)carbonyl 1-3-hexahydropyridinamine; (3 R )-1-{[2-(1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-({1-methyl-2-[1-(2-methylpropyl)-1 H - Indole-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-[(1-methyl-2-{1-[( 1-methyl-1 H -pyrazol-4-yl)methyl]-1 H -indol-2-yl}-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinium (3 R )-1-{[2-(5-chloro-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl }-3-hexahydropyridinamine; (3 R )-1-[(1-methyl-2-{1-[2-(methyloxy)ethyl]-1 H -indol-2-yl }-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; (3 R )-1-{[2-(6-bromo-1-ethyl-1 H -吲哚- 2- yl) -1-methyl -1 H - benzimidazol-5-yl] carbonyl} -3-six Pyridinamine; (3 R) -1 - ( {1- methyl-2- [1- (phenylmethyl) -1 H - indol-2-yl] -1 H - benzimidazol-5-yl }carbonyl)-3-hexahydropyridinamine; (3 R )-1-[(2-{1-[(4-iodophenyl)methyl]-1 H -indol-2-yl}-1- Methyl-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinamine; (3 R )-1-{[2-(1-ethyl-6-methyl-1 H -吲) Indole-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; (3 R )-1-({1-methyl-2-[ 1-(2-Pyridylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; (3 R )-1-({ 1-methyl-2-[1-(4-pyridylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; -[2-(5-{[(3 R )-3-amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1H-benzimidazol-2-yl)-1H-indole- 1-yl]ethanol; (3 R )-1-[(2-{1-[(4-chlorophenyl)methyl]-1H-indol-2-yl}-1-methyl-1H-benzene And imidazol-5-yl)carbonyl]-3-hexahydropyridinamine; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-6,7-dimethoxy) -1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl) (2-(6-ethoxy-1-ethyl-1H-indol-2-yl) -1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (( R )-3-aminohexahydropyridin-1-yl)(2-(1-((R)-) 3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)- 1H-benzo[d]imidazol-5-yl)methanone; ( R )-5-(3-aminohexahydropyridin-1-carbonyl)-2-(1-ethyl-1H-indole-2 -yl)-1-methyl-1H-benzo[d]imidazole-7-carbonitrile, hydrochloride; ( R )-(3-aminohexahydropyridin-1-yl)(7-bromo-2 -(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R) -(3-aminohexahydropyridine -1-yl)(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone; ( R )-( 3-aminohexahydropyridin-1-yl)(2-(1-(3,4-dichlorobenzyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazo-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-(4-methoxybenzyl)-1H-indole-2- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone; 1-({1-methyl-2-[1-(tetrahydro-2 H -pyran-4-) Methyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexa Hydropyridylamine; 1-{[2-(6-bromo-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}- 3-hexahydropyridinium; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl -1H-benzo[d]imidazol-5-yl)methanone; (3 R )-1-({1-methyl-2-[1-(2,2,2-trifluoroethyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinium hydrochloride; (( R )-3-aminohexahydropyridin-1-yl (2-(1-((R)-3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[ d]imidazol-5-yl)methanone, hydrochloride; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indole) -2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ( R )-(3-aminohexahydropyridine- 1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d Imidazol-5-yl)methanone, hydrochloride; ( 3S )-1-({1-methyl-2-[1-(phenylmethyl)-1 H -indol-2-yl] -1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinamine; ( S )-(3-aminohexahydropyridin-1-yl)(1-methyl-2-(1- Methyl-1H-indol-2-yl)-1H-benzo[d]imidazole- 5-yl)methanone; (1 R , 5 S )-3-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazole- 5-yl]carbonyl}-3-azabicyclo[3.1.0]hexan-1-amine; ( R )-(1-(2-aminoethyl)-2-(1-ethyl-1H-吲哚-2-yl)-1H-benzo[d]imidazol-5-yl)(3-aminohexahydropyridin-1-yl)methanone; ( R )-(3-aminohexahydropyridine- 1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethyl)-1H-benzo[d]imidazol-5-yl) Methyl ketone; (+/-)- cis- (3-amino-4-ethoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone; (+/-)-((cis)-3-amino-4-methoxyhexahydropyridin-1-yl (2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; cis- (3-amino- 2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)A Ketohydrochloride; cis- (5-amino-2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl- 1H-benzo[d]imidazol-5-yl)methanone hydrochloride; cis- (5-amino-2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H) -Indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone Acid salt; N-(azepan-3-yl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazole-5-formamide hydrochloride; (3-aminopyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1 -methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride; (3-aminocyclopentyl)(2-(1-benzyl-1H-indol-2-yl) -1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ((3 S ,4 R )-3-amino-4-hydroxyhexahydropyridin-1-yl)(7- Methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl) Methyl ketone; ((3 S , 4 R )-3-amino-4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2, 2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ((3 R , 4 S )-3-amine 4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indole-2- -1H-benzo[d]imidazol-5-yl)methanone; (3 R )-1-[(1-methyl-2-{1-[(1-methyl-1 H -pyrazole) 4-yl)methyl]-1 H -indol-2-yl}-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridinium hydrochloride; ( R )-(3 -aminohexahydropyridin-1-yl)(2-(1-ethyl-5-fluoro-1H-indole-2-) ) -1-methyl -1H- benzo [d] imidazol-5-yl) methanone, hydrochloride; (R) - (3- amino-hexahydro-1-yl) (2- (1 Ethyl-1H-indol-2-yl)-1-methyl-7-(pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ( R -5-(3-Aminohexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 7-Protonamine, hydrochloride; ( R )-(3-Aminohexahydropyridin-1-yl)(7-(dimethylamino)-2-(1-ethyl-1H-indole) 2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; 2-(1-ethyl-1H-indol-2-yl)-1 -methyl-N-(1,4-oxazepan-6-yl)-1H-benzo[d]imidazol-5-carboxamide hydrochloride; ((3 S ,4 R )-3 -amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazol-5-yl)methanone hydrochloride; ((3 S ,4 R )-3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)) -1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ((3 S , 4 R --3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone, Acid; (R) - (3- amino-hexahydro-1-yl) (2- (1-ethyl -1H- indol-2-yl) -1-methyl-7- (methylamine -1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ( R )-(3-aminohexahydropyridin-1-yl)(7-methoxy-2-() 1-(3-methoxypropyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ( R ) -(3-Aminohexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H -吲哚-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ( R )-(3-aminohexahydropyridin-1-yl)(7-A Oxy-2-(1-(2-methoxyethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, salt ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-7-methoxy- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; (( R )-3-aminohexahydropyridin-1-yl)(2-(1-(( S )-3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl) Ketone, hydrochloride; ( R )-2-(2-(5-(3-aminohexahydropyridine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d] Imidazol-2-yl)-1H-indol-1-yl) Carbonitrile, hydrochloride; (R) - (3- amino-hexahydro-1-yl) (7-ethyl-2- (1-ethyl -1H- indol-2-yl) -1- -1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; N- (azepan-3-yl)-2-(1-ethyl-1H-indole-2- yl) -1-methyl -1H- benzo [d] imidazole-5-acyl-amine; (S) - N - (azepan-3-yl) -2- (1-ethyl -1H-吲哚-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carboxamide; ( R )-N-(1-(2-(1-benzyl-1H-吲哚) -2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)-2-chloroethane; ( R )-(3-aminohexahydro Pyridin-1-yl)(2-(7-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )- (3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-5,6-dimethoxy-1H-indol-2-yl)-1-methyl-1H--benzene And [d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(3-ethyl-1H-indol-2-yl)-1 -methyl-1H-benzo[d]imidazol-5-yl)methanone; 1-{[2-(1-ethyl-7-methyl-1H-indol-2-yl)-1-yl -1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; N-(2-aminoethyl)-1-methyl-2-[1-(phenylmethyl)- 1H-indol-2-yl]-1H-benzimidazole-5-carboxamide; 1-{[2-(1 -ethyl-5-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; 1-{[2- (1-ethyl-4-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; ( R )- 2-(5-(3-Aminohexahydropyridine-1-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-1-ethyl-1H-indole-5- Benzonitrile; 2-(1-ethyl-1 H -indol-2-yl)-1-methyl- N- (hexahydropyridin-3-yl)-1 H -benzo[ d ]imidazole-5 -carbamamine; ( S )-(3-(aminomethyl)pyrrolidin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl- 1 H -benzo[ d ]imidazol-5-yl)methanone; (2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ] Imidazol-5-yl)(3-(methylamino)hexahydropyridin-1-yl)methanone; N- (2-aminoethyl)-2-(1-ethyl-1 H -indole -2-yl)-1-methyl-1 H -benzo[ d ]imidazole-5-carboxamide; (3,4- cis )-1-{[2-(1-ethyl-1 H) -吲哚-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3,4-hexahydropyridinediamine; (+/-)-((cis)- 4-amino-2-methylpyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 - yl) methanone, hydrochloride; (R) - (3- amine Hydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1,7-dimethyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-Aminohexahydropyridin-1-yl)(1-(3-aminopropyl)-2-(1-ethyl-1H-indol-2-yl)-1H-benzene And [d]imidazol-5-yl)methanone, bis -hydrochloride; ( R )-(3-aminohexahydropyridin-1-yl)(1-ethyl-2-(1-ethyl-) 1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; ( R )-(3-aminohexahydropyridin-1-yl)(2- (1-ethyl-1H-indol-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)methanone, hydrochloride; trans (+/ -)-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ] imidazol-5-yl)methanone; cis -((+/-)-3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indole) -2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; trans -((+/-)-3-amino-4-hydroxyhexahydropyridine-1 -yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; cis (+/-) 3-amino-4-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d] imidazol-5-yl) methanone; (3 R) -1 - { [2- (7- bromo-1-ethanone -1 H - indol-2-yl) -1-methyl -1 H - benzimidazol-5-yl] carbonyl} -3-pyridin-hexahydro-amine; 2- (5 - {[( 3 R) - 3-amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzoimidazol-2-yl)-1-ethyl-1 H -indole-7-ol; 2-( 5-{[(3 R )-3-amino-1-pyridinyl]carbonyl}-1-methyl-1 H -benzoimidazole-2-yl)-1-(cyclopropylmethyl) -1 H -indole-5-ol; 2-(5-{[(3 R )-3-amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazole- 2-yl)-1-ethyl-1 H -indole-6-ol; (3 R )-1-{[2-(1-ethyl-7-fluoro-1 H -indol-2-yl) )-1-methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1) -ethyl-4-fluoro-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; 2-(5-{[(3 R ) 3-amino-1-hexahydropyridyl]carbonyl}-1-methyl-1 H -benzoimidazol-2-yl)-1-ethyl-1 H -indole-7-carbonitrile; -amino-5,6-dihydropyridine-1( 2H )-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo [ d ]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7- (3-hydroxypropoxy)-1-methyl-1H-benzo[d]imidazole-5- ( R )-(3-Aminohexahydropyridin-1-yl)(7-ethoxy-2-(1-ethyl-1H-indol-2-yl)-1-yl -1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indole-2) -yl)-7-(2-methoxyethoxy)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridine -1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-(2-hydroxyethoxy)-1-methyl-1H-benzo[d]imidazole-5 -yl)methanone; ( R )-2-((5-(3-aminohexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1- Methyl-1H-benzo[d]imidazol-7-yl)oxy)acetonitrile; ( R )-2-((5-(3-aminohexahydropyridin-1-carbonyl)-2-(1- Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)oxy)acetamide; ( R )-(3-aminohexahydropyridine -1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone; +/-)-(3-Amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene And [d]imidazol-5-yl)methanone, trans- isomer; trans- 3-amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H) -吲哚-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl) Ketone, hydrochloride; (+/-)-(3-amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone, cis- isomer; cis- 3-amino-4-methylhexahydropyridin-1-yl) (2 -(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; (+/-)- cis 5-5-amino-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridine-3 -carbamamine; (3-amino-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene And [d]imidazol-5-yl)methanone hydrochloride; cis- (3-amino-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indole) -2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride; trans- (3-amino-5-methylhexahydropyridin-1-yl (2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride; (3-amino- 5-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl) Methyl ketone; (+/-)-((cis)-3,5-diaminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1 -methyl-1H-benzo[d]imidazol-5-yl)A Ketone hydrochloride; (+/-)-(( trans )-3-amino-5-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indole-2) -yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride; (3-amino-5-hydroxyhexahydropyridin-1-yl)(2-(1 -ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride, mixture of non-image isomers; (+/- ) -cis- 3-amino-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Hydropyridine-4-methionine hydrochloride; (3-aminohexahydropyridin-1-yl)(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H -benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-benzyl-1H-indol-2-yl) 1-(2-methoxyethyl)-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridin-1-yl)(2-( 1-benzyl-1H-indol-2-yl)-1-isopropyl-1H-benzo[d]imidazol-5-yl)methanone; ( R )-(3-aminohexahydropyridine- 1- yl) (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazol-5-yl) methane-thione hydrochloride; (cis Formula -(+/-)-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1H -benzo[d]imidazol-5-yl)A Ketone; (+/-)-(2-(aminomethyl)hexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl- 1 H -benzo[d]imidazol-5-yl)methanone; ((3 S ,4 R )-3-amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl) -1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone; ((3 S ,4 R )-3-amino-4- Fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone Hydrochloride; ((3 R , 4 S )-3-amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1- methyl-1H-benzo[d]imidazol-5-yl)methanone; ((3 R ,4 S )-3-amino-4-fluorohexahydropyridin-1-yl)(2-(1- Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride; ( R )-(3-aminohexahydropyridine- 1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5- Methyl ketone; ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl) -1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride; N- (3-azabicyclo[4.1.0]hept-1-yl)-2- (1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-A Amine; and (3-amino-piperidine-1-yl) (2- (1-Benzyl--1 H - indol-2-yl) -1-methyl -1H- benzo [d] imidazole - 5-based) ketone.

In one embodiment, the compound of the invention is selected from the list consisting of: (3R)-1-[2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-1, 3-benzoxazole-5-carbonyl]hexahydropyridin-3-amine; (3R)-1-{1-methyl-2-[1-(pyridin-3-ylmethyl)-1H-indole -2-yl]-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{1-methyl-2-[1-(2,2 ,2-trifluoroethyl)-1H-indol-2-yl]-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{2 -[1-(cyclopropylmethyl)-1H-indol-2-yl]-1-methyl-1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-(1-methyl-2-{1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-indol-2-yl}-1H-1 , 3-benzobisazole-5-carbonyl)hexahydropyridin-3-amine; (3R)-1-[2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-1,3-benzobisazole-5-carbonyl Hexahydropyridin-3-amine; (3R)-1-{2-[1-(cyclopropylmethyl)-1H-indol-2-yl]-7-methoxy-1-methyl- 1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{7-methoxy-1-methyl-2-[1-(2,2 ,2-trifluoroethyl)-1H-indol-2-yl]-1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-3-amine; (3S,4R)-3- Amino-1-{7-methoxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)-1H-indol-2-yl]-1H-1,3 -benzoxazole-5-carbonyl}hexahydropyridin-4-ol; and (3S,4R)-3-amino-1-{2-[1-(cyclopropylmethyl)-1H-indole 2-yl]-1-methyl-1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-4-ol; and salts thereof.

In one embodiment, the compound of the invention is selected from the list consisting of: (3R)-1-[2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-1, 3-benzoxazole-5-carbonyl]hexahydropyridin-3-amine; (3R)-1-{1-methyl-2-[1-(pyridin-3-ylmethyl)-1H-indole -2-yl]-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{1-methyl-2-[1-(2,2 ,2-trifluoroethyl)-1H-indol-2-yl]-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{2 -[1-(cyclopropylmethyl)-1H-indol-2-yl]-1-methyl-1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-(1-methyl-2-{1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-indol-2-yl}-1H-1 , 3-benzobisoxazol-5-carbonyl)hexahydropyridin-3-amine hydrochloride; (3R)-1-[2-(1-ethyl-1H-indol-2-yl)-7- Methoxy-1-methyl-1H-1,3-benzodiazol-5-carbonyl]hexahydropyridin-3-amine hydrochloride; (3R)-1-{2-[1-(cyclopropane Methyl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine hydrochloride salt; (3R)-1-{7-methoxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)-1H-indol-2-yl]-1H-1, 3-benzoxazole-5-carbonyl}hexahydropyridin-3-amine hydrochloride; (3S,4R)-3-amino-1-{7-methoxy-1-methyl-2-[ 1-(2,2,2-trifluoroethyl)-1H-indol-2-yl]-1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-4-ol; 3S,4R)-3-Amino-1-{2-[1-(cyclopropylmethyl)-1H-indol-2-yl]-1-methyl-1H-1,3-benzoic acid Zyrid-5-carbonyl}hexahydropyridin-4-ol hydrochloride.

Terms and definitions

The compound of the formula (I) and salts thereof are hereinafter referred to as "the compound of the present invention".

"Alkyl" means a saturated hydrocarbon chain having the indicated number of carbon atoms. For example, C _1-6 alkyl means an alkyl group having 1 to 6 carbon atoms, for example 1 to 3 carbon atoms. For example, C _2-6 alkyl refers to an alkyl group having 2 to 6 carbon atoms, for example 2 to 3 carbon atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have 1, 2 or 3 branches. "Alkyl" includes methyl, ethyl, isopropyl and isobutyl.

"Cycloalkyl" means a saturated hydrocarbon ring having the specified number of member atoms. For example, C _3-6 cycloalkyl refers to a cycloalkyl group having 3 to 6 member atoms, for example 3 member atoms. "Cycloalkyl" includes cyclopropyl.

"Imagewise isomer excess" (ee) is an excess of one mirror image isomer relative to the other, expressed as a percentage. In the racemic modified form, since the two mirror image isomers are present in equal amounts, the image isomer excess is 0 (0% ee). However, if a mirror image isomer is enriched such that it constitutes 95% of the product, the excess of the mirror image isomer may be 90% ee (the amount of enriched mirror image isomer minus 95% minus the amount of another mirror isomer) 5%).

"Image entropy enrichment" means a product having a total amount of image isomers (ee) greater than zero. For example, "mirror isomer enrichment" refers to a product having an amount of image isomer excess greater than 50% ee, greater than 75% ee, and greater than 90% ee.

"Image isomer pure" means a product having an excess of mirror image isomers of 99% or greater.

"Half-life" or "half-lives" means half of the substance The time required to convert in vitro or in vivo to another chemically different substance.

"Halo" means a halogen group such as fluorine, chlorine, bromine or iodine.

"Haloalkyl" means an alkyl group as defined above wherein at least one hydrogen atom is replaced by a halogen group. The "C _1-6 haloalkyl group" means a C _1-6 alkyl group in which at least one hydrogen atom is replaced with a halogen group. Examples of "haloalkyl" are trifluoromethyl or 2,2,2-trifluoroethyl.

"Heterocycle" and "heterocyclyl" are saturated or unsaturated monocyclic aliphatic rings containing 5, 6 or 7 ring members (including 1 or 2 heteroatoms) or containing 5, 6 or 7 ring members. A saturated or unsaturated bicyclic aliphatic ring (including 1 or 2 heteroatoms). In certain embodiments, the "heterocyclyl" is saturated. In other embodiments, the "heterocyclyl" is unsaturated. A "heterocyclic group" containing one or more hetero atoms may contain different hetero atoms. "Heterocyclyl" may be substituted by one or more substituents as defined herein. The "heterocyclic group" includes a hexahydropyridyl group, a tetrahydropyranyl group, a hydrazinyl group, a oxazinyl group, an azabicyclo[3.1.0]hexyl group or an azabicyclo[4.1.0]heptyl group.

"Heteroaryl" means an aromatic ring containing from 1 to 3 heteroatoms as a member of a ring. "Heteroaryl" containing more than one hetero atom may contain different heteroatoms. "Heteroaryl" may be substituted by one or more substituents, if any, as defined herein. A "heteroaryl" ring has 5 or 6 member atoms. "Heteroaryl" includes pyridyl and pyrazolyl.

"Hetero atom" means a nitrogen, sulfur or oxygen atom such as a nitrogen atom or an oxygen atom.

"Member atom" means one or more atoms forming a chain or a ring. If more than one member atom is present in the chain and in the ring, each member atom is covalently bonded to an adjacent member atom in the chain or ring. The atom constituting the substituent on the chain or ring is not a member atom in the chain or ring.

"Substituted" when referring to a group indicates that the hydrogen atom attached to the member atom within the group is replaced. It will be understood that the term "substituted" includes the following premise that the substitution results in a stable compound (ie, does not spontaneously undergo a transition (eg, rearrangement, cyclization, or elimination) based on the permissible valence of the substituted atom and the substituent. In certain embodiments, a single atom may be substituted with more than one substituent, as long as the substitution is based on the permissible value of the atom. Suitable to replace The radicals are defined herein for each substituted or optionally substituted group.

"Pharmaceutically acceptable" means that they are suitable for use in connection with human and animal tissue and are not toxic, irritating, or otherwise problematic or commensurate with reasonable benefits/risk ratios within reasonable medical judgment. , materials, compositions and dosage forms.

Throughout the following description and claims, the words "comprise" or variations (such as "comprises" and "comprising") are understood to include the integer or step, unless the context requires otherwise. Or an integer group, but does not exclude any other integer or step or integer or group of steps.

As used herein, the symbols and conventions used in such processes, protocols, and examples are consistent with those used in contemporary scientific literature, such as the Journal of the American Chemical Society . All starting materials were obtained from commercial suppliers and used without further purification unless otherwise stated. In particular, the following abbreviations may be used in the examples and throughout the specification.

abbreviation

Within the scope of "compounds of the invention" are all solvates (including hydrates), complexes, polymorphs, prodrugs, radiolabeled derivatives and stereoisomers of the compounds of formula (I) and salts thereof.

The compounds of the invention may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or amorphous form or as a mixture thereof. For compounds of the invention in crystalline form, it will be apparent to those skilled in the art that a pharmaceutically acceptable solvate can be formed in which solvent molecules are incorporated into the crystalline crystal lattice during crystallization. The solvate may be a non-aqueous solvent such as ethanol, isopropyl alcohol, N,N-dimethylhydrazine (DMSO), acetic acid, ethanolamine and ethyl acetate, or it may involve water as a solvent incorporated into the crystal lattice. . Solvates in which the water is incorporated into the solvent in the crystalline crystal lattice are often referred to as "hydrates". Hydrate includes Stoichiometric hydrates and compositions containing variable amounts of water. The present invention includes all such solvates.

It will be further appreciated that certain compounds of the invention, including their various solvates, which are present in crystalline form, may exhibit polymorphism (i.e., the ability to occur in different crystalline structures). These different crystal forms are often referred to as "polymorphs". The invention includes such polymorphs. Polymorphs have the same chemical composition, but the filling, geometric arrangement, and other descriptive properties of the crystalline solid are different. Thus, polymorphs can have different physical properties such as shape, density, hardness, deformability, stability, and solubility properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns that can be used for identification. It will be appreciated that different polymorphs can be produced by, for example, changing or adjusting the reaction conditions or reagents used in the manufacture of the compounds. For example, temperature, pressure or solvent changes can produce polymorphs. In addition, under certain conditions, one polymorph can spontaneously transform into another polymorph.

The present invention also encompasses isotopically-labeled compounds, and compounds of the formula (I) and salts thereof, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. the same. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen and fluorine, such as ³ H, ¹¹ C, ¹⁴ C and ¹⁸ F.

The compound of formula (I) contains one or more asymmetric centers (also referred to as chiral centers) and, therefore, may be in the form of individual mirror image isomers, non-image isomers, or other stereoisomers or in a mixture thereof. presence. A chiral center (eg, a chiral carbon atom) can also be present in a substituent such as an alkyl group. If stereochemistry of the chiral center present in formula (I) or any of the chemical structures illustrated herein is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof. Thus, a compound of formula (I) containing one or more chiral centers can be in racemic modified form (including racemic mixtures and racemates), enantiomerically enriched mixtures, or mirror image isomers pure Individual stereoisomeric forms are used.

Can be resolved by one or more asymmetries by methods known to those skilled in the art Individual stereoisomers of the compounds of formula (I). For example, the resolution can be carried out by: (1) by forming a non-image isomer salt, a complex or other derivative; (2) by selectively reacting with a stereoisomer-specific reagent, such as Oxidizing or reducing by an enzyme; or (3) by gas-liquid or liquid in a chiral environment, for example, on a chiral carrier having a chiral ligand (for example, cerium oxide) or in the presence of a chiral solvent Phase chromatography. It will be appreciated that when the desired mirror image isomer is converted to another chemical entity by one of the above separation procedures, another step is required to release the desired form. Alternatively, a specific mirror image isomer can be synthesized by asymmetric synthesis using an optically active reagent, matrix, catalyst or solvent or by asymmetric conversion of one of the mirror image isomers to another mirror image isomer.

It is to be understood that the compounds of formula (I) and their salts herein are referred to as compounds of formula (I) in the form of the free base or in the form of their salts, for example in the form of their pharmaceutically acceptable salts. Thus, in one embodiment, the invention relates to a compound of formula (I) in the form of a free base. In another embodiment, the invention relates to compounds of formula (I) and salts thereof. In still another embodiment, the invention is directed to a compound of formula (I), and pharmaceutically acceptable salts thereof.

It will be appreciated that pharmaceutically acceptable salts of the compounds of formula (I) can be prepared. Indeed, in certain embodiments of the invention, the pharmaceutically acceptable salts of the compounds of formula (I) may be preferred over the individual free bases, as such salts impart greater stability or solubility to the molecule, This promotes formulation into a dosage form. Accordingly, the invention further relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

The term "pharmaceutically acceptable salt" as used herein refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects. Such pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free base form with the appropriate acid.

Salts and solvates having non-pharmaceutically acceptable relative ionic or associative solvents are within the scope of the invention, for example, as intermediates in the preparation of other compounds of formula (I) and pharmaceutically acceptable salts thereof. Accordingly, one embodiment of the invention encompasses compounds of formula (I) and salts thereof.

The compounds of formula (I) contain a basic functional group and are therefore capable of forming a pharmaceutically acceptable acid addition salt by treatment with a suitable acid. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochlorides, hydrobromides, nitrates, methyl nitrates, sulfates, hydrogen sulfates, amine sulfonates, phosphates, acetates, glycolic acids Salt, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate, Citrate, salicylate, p-amyl sulphate, glycolate, lactate, heptanoate, phthalate, oxalate, succinate, benzoate, o -acetyl Oxybenzoic acid salt, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, naphthate, hydroxynaphthate , mandelate, stannate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutaric acid Acid salt, glutamate, estolate, methanesulfonate (methanesulfonate), ethanesulfonate (ethanesulfonate), 2-hydroxyethanesulfonate, benzenesulfonic acid Salt (benz enesulfonate or besylate), for - amine benzenesulfonate, p - toluenesulfonate (tosylate) and naphthalene-2-sulfonate.

Compound preparation

The compounds of the invention can be made by a variety of methods, including standard chemical methods. Unless otherwise indicated, any previously defined variable may continue to have the previously defined meaning. Interpretive general synthetic methods are set forth in the schemes below and can be readily adapted to prepare other compounds of the invention. Specific compounds of the invention are prepared in the Examples section.

The compound of formula (I) can be prepared by coupling a diamino-(hetero)aryl compound of formula (II) with a carboxylic acid of formula (III) according to Scheme 1.

plan 1

Thus, in a first aspect, there is provided a process for the preparation of a compound of formula (I) by reacting a compound of formula (II) with a compound of formula (III) wherein Y, X, R ₁ and R _{3 -} R ₁₁ are The coupling is accomplished as described above and thereafter, if desired, to prepare a salt of the formed compound.

For example, a coupling agent (eg, HATU) and a suitable base (eg, DIPEA) are added to a solution of a compound of formula (III) in a suitable solvent (eg, N,N-dimethylformamide), followed by formula (II) The compound is stirred at a suitable temperature (e.g., ambient temperature) for a suitable length of time (e.g., 1-3 hours). The indoleamine intermediate is obtained using conventional purification methods. The guanamine intermediate is dissolved in a suitable solvent such as toluene and treated with a suitable acid (e.g., acetic acid) at a suitable temperature (e.g., reflux) for a suitable length of time (e.g., 1.5 h). Standard purification procedures yield compounds of formula (I).

Alternatively, a compound of formula (I) can be prepared by coupling an amide-substituted amino-(hetero)aryl group of formula (IV) with an aldehyde of formula (V) according to Scheme 2.

Thus, in still another aspect, there is provided a process for the preparation of a compound of formula (I) by reacting a compound of formula (IV) with a compound of formula (V) wherein Y, X, R ₁ and R _{3 -} R ₁₁ are The coupling is accomplished as described above and thereafter, if desired, to prepare a salt of the formed compound.

For example, a solution of a compound of formula (IV) in a suitable solvent (eg, ethanol) is added to a solution of a suitable solvent (eg, an ethanol/water mixture) of sodium bisulfite and a compound of formula (V), and the reactants are suitably employed. Stir for a suitable length of time (eg, overnight) at a temperature (eg, elevated temperature, such as 85 ° C). The reaction mixture is subjected to standard processing and purification to give a compound of formula (I).

Alternatively, a compound of formula (I) wherein X is O may be prepared by reacting an amine of formula (VI) according to Scheme 3. The carboxylic acid of formula (VII) is coupled for preparation.

Compounds of formula (I) wherein X is S can be prepared from the corresponding guanamines (compounds of formula (I) wherein X is O) according to Scheme 10.

Thus, in a further aspect, there is provided a process for the preparation of a compound of formula (I) by reacting an amine of formula (VI) with a carboxylic acid of formula (VII) wherein Y, X, R ₁ and R ₃ - The R ₁₁ is as defined above) coupled and thereafter (if desired) to prepare a salt of the formed compound.

For example, a peptide coupling agent (for example, hexafluorophosphate o-(7-azabenzotriazole) is added to a solution of the compound of formula (VII) in a suitable solvent such as N,N-dimethylformamide. -1-yl)-N,N,N',N'-tetramethyluronium hydride (HATU)) and a suitable base (such as diisopropylethylamine (DIPEA)), then a compound of formula (VI), and The reactants are stirred at a suitable temperature (e.g., ambient temperature) for a suitable length of time (e.g., 1-3 hours).

The compound of the formula (II) can be prepared from the ester (XIII) according to Scheme 4 by treating the ester with an amine (IX) to give the ester (X), followed by treating the ester (X) with an amine (VI) to give a nitro group. - Compound (IV), and nitro-compound (IV) is reduced to give amine (II).

For example, the compound of formula (XIII) is dissolved in a suitable solvent (for example DMF) and amine (IX) is added thereto. The reaction is stirred at a suitable temperature (e.g., elevated temperature, e.g., 80 ° C) for a suitable length of time (e.g., 3 h). The compound of formula (X) is isolated using standard purification techniques. The nitro compound (X) is dissolved in a suitable solvent such as THF and saponified using, for example, lithium hydroxide to give the free acid after standard purification techniques. The free acid and the appropriate peptide coupling agent (e.g., HATU) are dissolved in a suitable solvent (e.g., DMF) and treated with a suitable tertiary amine (e.g., DIPEA), followed by the addition of the amine (VI). The mixture is stirred at a suitable temperature (e.g., ambient temperature) for a suitable length of time (e.g., 1.5 h). The urethane compound (VI) is isolated by standard purification techniques. The urethane compound (VI) in a suitable solvent (for example, ethanol) is added to a rinsed hydrogenation flask containing a suitable hydrogenation catalyst (for example, palladium on carbon), and stirred under a hydrogen atmosphere for a suitable length of time (for example, 44 h). . The catalyst was removed by filtration and the diamine (II) was obtained via standard purification conditions.

Amines of formula (IX) are commercially available (for example from Sigma Aldrich).

A compound of formula (III) wherein R ₄ is other than H can be obtained according to Scheme 5 from carboxylic acid (XI) (a compound of formula (III) wherein R ₄ is H) by protecting the carboxylic acid to form an ester (XII) After alkylation to give the protected ester (XIII), followed by saponification to give the carboxylic acid (III).

The carboxylic acid of the formula (XI) is commercially available. Some of the esters of formula (XII) are commercially available.

For example, a compound of formula (XII) in a suitable solvent (e.g., DMF) is treated with a base (e.g., sodium hydride) at a suitable temperature (e.g., 0 °C) for a suitable length of time (e.g., 1 h). Addition of a suitable alkylating agent R ₄ -Z (e.g. ethyl iodide) was added and the mixture was at a suitable temperature (e.g., 0 deg.] C) a suitable length of time (e.g. over 2 days) with stirring. The N-alkylated ester (XIII) is isolated using standard purification techniques. The ester (XIII) is dissolved in a suitable solvent (eg water/methanol/THF mixture) and a base (eg lithium hydroxide monohydrate) is added and the mixture is stirred at a suitable temperature (eg ambient temperature) for a suitable length of time (eg overnight). The carboxylic acid (III) is obtained using standard purification techniques.

The compound of the formula (VIII) can be produced from the corresponding carboxylic acid (XIV) according to Scheme 6 by nitrating the carboxylic acid to give the nitro-compound (XV), followed by esterification to give (VIII).

The carboxylic acid of the formula (XIV) and the many acids of the formula (XV) and the ester of the formula (VIII) are commercially available.

For example, a compound of formula (XIV) is used at a suitable temperature (eg -20 ° C) with concentrated sulfuric acid The fuming nitric acid is treated and added and the mixture is warmed to a suitable temperature (e.g., ambient temperature) for a suitable length of time (e.g., 2 hours). Standard post-treatment gives the nitrated carboxylic acid (XV). The compound (XV) is dissolved in a suitable protic solvent (e.g., methanol) and treated with an acid (e.g., hydrochloric acid) at a suitable temperature (e.g., elevated temperature, e.g., hydrochloric acid) for a suitable length of time (e.g., overnight). After acidification and standard workup, the ester (VIII) is obtained.

The aldehyde of formula (V) can be obtained from formula (XVI) according to Scheme 7. The aldehyde of formula (V) can also be prepared by alkylation of an aldehyde of the formula (XVIII).

For example, the compound of formula (XVI) is dissolved in a suitable solvent (eg, DMF) and treated with a suitable base (eg, sodium hydride) at a suitable temperature (eg, ambient temperature) for a suitable length of time (eg, 2 minutes). The mixture is then treated with a suitable alkylating agent (e.g., ethyl iodide) at a suitable temperature (e.g., ambient temperature) for a suitable length of time (e.g., 4.5 h). Standard post-treatment gives the formula (XVII). The hydrazine (XVII) is dissolved in a suitable solvent (e.g., anhydrous THF) at a suitable temperature (e.g., 0 °C). A suitable base (e.g., n-butyllithium in hexane) is then added at a suitable temperature (e.g., 0 °C) over a suitable length of time (e.g., 10 minutes). The reaction is stirred at a suitable temperature (e.g., ambient temperature) for a suitable length of time (e.g., 1.5 h). The reaction is cooled to a suitable temperature (e.g., -78 °C) and DMF is added and the reaction is stirred for a further period of time (e.g., 2.5 hours). The reaction is quenched by the addition of a suitable reagent such as a sodium bicarbonate solution. The aldehyde of formula (V) can be obtained using standard purification techniques.

The carboxylic acid of the formula (VII) can be obtained according to Scheme 8 from a hydrazine substituted with a corresponding formula (XX) which can be obtained by reacting an aldehyde of the formula (V) with a brominated compound of the formula (XIX).

For example, a solution of sodium disulfate sulphate in a suitable solvent such as water is added to a microwave vial, and a nitro compound of formula (XIX) and an aldehyde of formula (V) are added to a suitable solvent (eg, ethanol). Solution. The reaction vessel is sealed and heated at a suitable temperature (e.g., 100 °C) using microwaves for a suitable length of time (e.g., 5 hours). The reaction mixture is diluted with a suitable solvent (e.g., DCM), followed by standard purification techniques to afford the compound of formula (XX).

A compound of formula (XX), a suitable acid protecting group (eg methanol), a suitable base (eg DIPEA) and a suitable nucleophilic catalyst (eg DMAP) and a suitable catalyst (eg hexacarbonyl) in a microwave vessel Molybdenum and ethoxylated (2-(di-o-tolylphosphino)benzyl palladium) are dissolved in a suitable solvent such as 1,4-dioxane. The vessel is sealed and at a suitable temperature (eg 180 ° C) The microwave is heated for a suitable length of time (e.g., 3 hours) followed by cooling. Standard purification techniques yield an ester of formula (XXI).

Add a suitable base (such as lithium hydroxide) to a solution of the ester of formula (XXI) in a suitable solvent (eg THF/water mixture) and stir the mixture at a suitable temperature (eg room temperature) for a suitable length of time (eg 68 h) ). The reaction mixture is filtered and then acidified using a suitable acid such as hydrochloric acid. Standard work-up gives the carboxylic acid of formula (VII).

Alternatively, the carboxylic acid derivative of the formula (VII) can be produced according to Scheme 9 by coupling a nitro compound (X) with an aldehyde (V) to give an ester (XXI), followed by saponifying the ester (XXI) to give Carboxylic acid derivative (VII).

Compounds of formula (I) wherein X is S may be derived from the corresponding guanamine (compound of formula (I) wherein X is O) according to Scheme 10 by using Lawesons reagent and acetonitrile in a suitable solvent at a suitable temperature (for example, reflux temperature) For example, dimethoxyethane) is obtained by treating for a suitable length of time (for example, 1 h). Standard purification yields thioguanamine (a compound of formula (I) wherein X is S).

Thus, in still another aspect, there is provided a process for the preparation of a compound of formula (I) wherein X is S by treating a compound of formula (I) with Lawessons reagent wherein X is O and wherein Y, R ₁ and R ₃ -R ₁₁ is as defined above) and thereafter (if desired) to prepare a salt of the formed compound.

Examples of other protecting groups that can be used in the synthetic routes described herein and their removal can be found in TW Greene "Protective Groups in Organic Synthesis", 4th edition, J. Wiley and Sons, 2006 , which relates to such procedures. This is incorporated herein by reference.

For any of the reactions or processes described above, conventional methods of heating and cooling may be employed, such as a temperature-regulated oil bath or a temperature-regulating heat block, and an ice/salt bath or a dry ice/acetone bath, respectively. Conventional separation methods can be used, for example, extraction or extraction from aqueous or non-aqueous solvents into aqueous or non-aqueous solvents. A conventional method of drying an organic solvent, a solution or an extract may be employed, for example, shaking with anhydrous magnesium sulfate or anhydrous sodium sulfate or passing through a hydrophobic glass. If desired, conventional purification methods such as crystallization and chromatography (e.g., ceria chromatography or reverse phase chromatography) can be used. Crystallization can be carried out using a conventional solvent such as ethyl acetate, methanol, ethanol or butanol or an aqueous mixture thereof. It will be appreciated that the specific reaction times and temperatures can generally be determined by reaction monitoring techniques such as thin layer chromatography and LC-MS.

Where appropriate, individual isomeric forms of the compounds of the invention can be prepared as individual isomers using conventional procedures (e.g., fractional crystallization of a non-mironomer derivative or chiral high performance liquid chromatography (Chiral HPLC)).

The absolute stereochemistry of the compound can be determined using conventional methods such as X-ray crystallography or VCD (Vibration Circular Dichroism) analysis.

Instructions

The compounds of the invention are inhibitors of PAD4. Compounds that inhibit PAD4 are useful in the treatment of various conditions such as rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus and psoriasis.

The method of treatment of the present invention comprises administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Individual embodiments of the invention include methods of treating any of the above mentioned conditions by administering to a patient in need thereof a safe and effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Reference to a "treatment" as used herein means: (1) improving or preventing one or more biological manifestations of a disorder or condition, (2) interfering with (a) causing or being responsible for one of the biological cascades of the disorder. Or multiple points, or (b) one or more biological manifestations of the condition, (3) mitigating one or more of the symptoms or effects associated with the condition, or (4) slowing one or more of the condition or condition Progress in biological performance.

As indicated above, "treatment" of a condition includes prevention of the condition. It should be understood that "prevention" is not an absolute term. In medicine, "prevention" is understood to mean the prophylactic administration of a drug to substantially reduce the likelihood or severity of the condition or its biological manifestation, or to delay the onset of the condition or its biological manifestations.

As used herein, "safe and effective amount" when referring to a compound of formula (I) or a pharmaceutically acceptable salt or other pharmaceutically active agent thereof, is meant to be sufficient to treat the condition of the patient and is low enough to avoid seriousness within the scope of sound medical judgment. The amount of side effects (in a reasonable benefit/risk ratio) of the compound. The safe and effective amount of the compound will vary depending on the particular compound selected (eg, the efficacy, potency, and half-life of the compound will be considered); the route of administration chosen; the condition being treated; the severity of the condition being treated; the patient being treated Age, size, weight and physical condition; medical record of the patient to be treated; duration of treatment; nature of concurrent therapy; expected therapeutic effect; and similar factors, but can be routinely determined by those skilled in the art.

As used herein, "patient" refers to humans (including adults and children) or other animals. In one embodiment, the "patient" is a human.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Parenteral administration refers to a route of administration that is not enteral or transdermal, and is usually by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhalation, and intranasal administration. Inhalation refers to administration into the lungs of a patient, whether by inhalation through the mouth or via the nasal passages. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered orally. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered topically. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered by inhalation. In still another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered intranasally.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered once or according to a dosing regimen, wherein multiple doses are administered at different time intervals for a given period of time. For example, the dose can be administered once, twice, three times or four times a day. In one embodiment, the dosage system is administered once a day. In yet another embodiment, the dosage system is administered twice daily. The dose can be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable administration regimens for a compound of formula (I) or a pharmaceutically acceptable salt thereof depend on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, as determined by those skilled in the art. In addition, suitable administration regimens of the compound of formula (I) or a pharmaceutically acceptable salt thereof, including the duration of administration of such regimen, will depend on the condition being treated, the severity of the condition being treated, the age and The condition, the medical history of the patient to be treated, the nature of the concurrent therapy, the desired therapeutic effect, and similar factors within the knowledge and experience of those skilled in the art. Those skilled in the art will further appreciate that a suitable dosing regimen may require adjustment of the individual patient's response to the dosing regimen or individual patient needs to change over time.

A typical daily dose can vary depending on the particular route of administration chosen. A typical daily dose for oral administration is in the range of from 0.1 mg to 10 mg/kg of total body weight, for example from 1 mg to 5 mg/kg. For example, the daily dose for oral administration can range from 5 mg to 1 g per patient, such as from 5 mg to 500 mg per patient, or from 5 mg to 250 mg.

Alternatively, the compound of formula (I) can be administered as a prodrug. As used herein, a "prodrug" of a compound of formula (I) is a functional derivative of a compound which releases a compound of formula (I) in vivo, after administration to a patient. Administration of a compound of formula (I) as a prodrug may enable one skilled in the art to carry out one or more of the following: (a) improving the activity of the compound in vivo; (b) modifying the compound in vivo The duration of action; (c) improving the transport or distribution of the compound in vivo; (d) improving the solubility of the compound in vivo; and (e) overcoming the side effects or other difficulties encountered by the compound. Typical functional derivatives for the preparation of prodrugs include modified forms of compounds which are chemically or enzymatically cleaved in vivo. Such modified forms (including phosphate esters, decylamines, esters, thioesters, carbonates, and urethane formulations) are well known to those skilled in the art fat.

Accordingly, the invention provides a method of treating a condition mediated by PAD4 activity comprising administering to a patient in need thereof a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment, the condition mediated by PAD4 activity is selected from the group consisting of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, skin erythema Lupus and psoriasis. In yet another embodiment, the condition mediated by PAD4 activity is rheumatoid arthritis. In yet another embodiment, the condition mediated by PAD4 activity is systemic lupus. In yet another embodiment, the condition mediated by PAD4 activity is vasculitis. In yet another embodiment, the condition mediated by PAD4 activity is cutaneous lupus erythematosus. In yet another embodiment, the condition mediated by PAD4 activity is psoriasis.

In one embodiment, a method of treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus or psoriasis is provided, the method comprising The patient is administered a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment, a method of treating rheumatoid arthritis is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, a method of treating systemic lupus is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. In one embodiment, a method of treating vasculitis comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In one embodiment, a method of treating cutaneous lupus erythematosus is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, a method of treating psoriasis is provided, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition mediated by PAD4 activity. In another embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, sac Sexual fibrosis, asthma, cutaneous lupus or psoriasis. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of rheumatoid arthritis. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of systemic lupus. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of vasculitis. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of cutaneous lupus erythematosus. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of psoriasis. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a condition mediated by PAD4 activity. In another embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colon An agent for inflammation, cancer, cystic fibrosis, asthma, cutaneous lupus, or psoriasis. In another embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of rheumatoid arthritis. In another embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of systemic lupus. In another embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of vasculitis. In another embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of cutaneous lupus erythematosus. In another embodiment, the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of psoriasis. In yet another embodiment, the present invention provides A pharmaceutical composition for treating or preventing a condition mediated by PAD4 activity and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, skin erythema Lupus or psoriasis and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention provides a pharmaceutical composition for treating or preventing rheumatoid arthritis and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention provides a pharmaceutical composition for treating or preventing systemic lupus and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention provides a pharmaceutical composition for treating or preventing vasculitis and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention provides a pharmaceutical composition for treating or preventing cutaneous lupus erythematosus and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention provides a pharmaceutical composition for treating or preventing psoriasis and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

combination

The compound of formula (I) and its pharmaceutically acceptable salts will generally, but not necessarily, be formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, in another aspect, a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients is provided. In still another aspect, the invention relates to a pharmaceutical composition for treating or preventing a condition mediated by PAD4 activity and comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the present invention can be prepared and packaged in bulk form, wherein a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be extracted and subsequently administered to a patient with, for example, a powder or syrup. Alternatively, the pharmaceutical compositions of the present invention may be prepared and packaged in unit dosage form, wherein each physically discrete unit comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. When prepared in unit dosage form, the pharmaceutical compositions of the invention may generally contain, for example, 0.25 mg to 1 g, or 0.5 mg to 500 mg, or 1 mg to 100 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition of the present invention usually contains a compound of the formula (I) or a pharmaceutically acceptable salt thereof.

"Pharmaceutically acceptable excipient" as used herein means a pharmaceutically acceptable substance, composition or vehicle which is administered in the form or consistency of a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed so as to avoid the substantial reduction in the potency of the compound of formula (I) or its pharmaceutically acceptable salt when administered to a patient and Produces an interaction that is not a pharmaceutically acceptable pharmaceutical composition. In addition, each excipient must of course be pharmaceutically acceptable, for example of sufficiently high purity.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients will generally be formulated in a dosage form suitable for administration to a patient by the desired route of administration. For example, the dosage forms include those suitable for: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, Small sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, For example, suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Additionally, suitable pharmaceutically acceptable excipients can be selected for their particular function in the composition. For example, certain pharmaceutically acceptable excipients can be selected for their ability to promote the production of a homogeneous dosage form. Certain pharmaceutically acceptable excipients can be selected for their ability to promote the production of stable dosage forms. Certain pharmaceutically acceptable excipients for which one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof are carried or transported to another part of the body after administration to a patient The ability of the organ or part to choose. Certain pharmaceutically acceptable excipients can be selected for their ability to enhance patient compliance Choose.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents Cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anti-caking agents, moisturizers, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, and stability Agents, surfactants and buffers. Those skilled in the art will appreciate that depending on how many excipients are present in the formulation and which other excipients are present in the formulation, certain pharmaceutically acceptable excipients may serve more than one function and may Alternative features.

Those skilled in the art have the knowledge and skill in the art to be able to select a suitable amount of suitable pharmaceutically acceptable excipient for use in the present invention. In addition, there are a variety of resources available to those skilled in the art that exemplify pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the industry are described in Remington's Pharmaceutical Sciences (Mack Publishing Company) .

Accordingly, in another aspect, the invention relates to a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, comprising a mixture Ingredients. Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof can be prepared, for example, by mixing at ambient temperature and atmospheric pressure.

In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, will be formulated for oral administration. In another embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, will be formulated for administration by inhalation. In still another embodiment, the compound of formula (I) or a pharmaceutically acceptable compound thereof The salt received will be formulated for intranasal administration.

In one aspect, the invention relates to a solid oral dosage form (e.g., a lozenge or capsule) comprising a safe and effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (eg corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (eg microcrystalline cellulose), Calcium sulfate and calcium hydrogen phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (eg corn starch, potato starch and pregelatinized starch), gelatin, gum arabic, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (eg microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The oral solid dosage form can further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

If appropriate, the dosage unit formulation for oral administration can be microencapsulated. The compositions may also be prepared for extended or sustained release by, for example, coating or embedding the particulate material in a polymer, wax or the like.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be coupled to a soluble polymer as a targetable pharmaceutical carrier. Such polymers may include polyvinylpyrrolidone, piperene copolymer, polyhydroxypropylmethylpropionamine-phenol, polyhydroxyethylaspartamide phenol or polyoxyethylene polycarboxylate substituted with palm ruthenium residues. Acetylic acid. Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyε-caprolactone, polyhydroxybutyrate, poly Crosslinked or amphiphilic block copolymers of orthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

In another aspect, the invention is directed to a liquid oral dosage form. Oral liquids (e.g., solutions, syrups, and elixirs) can be prepared in unit dosage form such that a given amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Syrup can be obtained by using a compound of formula (I) or The pharmaceutically acceptable salts are prepared by dissolving in an appropriately flavored aqueous solution, and the elixirs are prepared by using a non-toxic alcohol vehicle. The suspension may be formulated by dispersing a compound of formula (I) or a pharmaceutically acceptable salt thereof in a non-toxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether), preservatives, flavor additives (such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners) may also be added. And so on).

In another aspect, the invention relates to a dosage form suitable for administration to a patient by inhalation, for example in the form of a dry powder, aerosol, suspension or solution composition.

A dry powder composition for delivery to the lung by inhalation typically comprises a compound of formula (I) in the form of a fine powder, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients in the form of a fine powder. . Pharmaceutically acceptable excipients which are especially suitable for use in dry powders are known to those skilled in the art and include lactose, starch, mannitol and monosaccharides, disaccharides and polysaccharides. Fine powders can be prepared, for example, by micronization and milling. Generally, the size is reduced (e.g. micronised) compound by the _IC50 values from about 1 to about 10 microns D (e.g. as measured using the laser diffraction) is defined.

The dry powder can be administered via a reservoir dry powder inhaler (RDPI) having a reservoir suitable for storing multiple (unmeasured doses) of the medicament in dry powder form. The RDPI typically includes means for metering each dose of medicament from the reservoir to the delivery location. For example, the metering member can include a metering cup that can be moved from a first position in which the reservoir is filled with the medicament to a second position at which the metered dose can be used by the patient for inhalation.

Alternatively, the dry powder can be presented in a multi-dose dry powder inhaler (MDPI) in a capsule (eg, gelatin or plastic), column or blister pack. MDPI is an inhaler in which a medicament is contained in a multi-dose pack containing (or otherwise carrying) a plurality of defined doses (or portions thereof) of the medicament. When the dry powder is presented in the form of a blister pack, it comprises a plurality of blisters for containing the medicament in the form of a dry powder. The blister is typically arranged in a regular manner to facilitate release of the agent therefrom. For example, the blister can be arranged in a generally circular manner on the disc shaped blister pack, or the blister can be extended in form, for example comprising a strip or strip. Each capsule, column or blister can be (for example) A compound of formula (I), or a pharmaceutically acceptable salt thereof, is included between 200 μg and 10 mg.

The aerosol can be formed by suspending or dissolving a compound of formula (I) or a pharmaceutically acceptable salt thereof in a liquefied propellant. Suitable propellants include halocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1, 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane Alkanes, butanes, isobutanes and pentanes. Aerosols comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof will typically be administered to a patient via a metered dose inhaler (MDI). Such devices are well known to those skilled in the art.

Aerosols may contain additional pharmaceutically acceptable excipients, such as surfactants, lubricants, cosolvents, and other excipients, which are typically employed with MDI to improve the physical stability of the formulation, improve valve performance, and improve Solubility or improved taste.

Accordingly, as a further aspect of the present invention, there is provided a pharmaceutical aerosol formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a fluorocarbon or hydrogen-containing chlorofluorocarbon as a propellant, optionally In combination with a surfactant and/or a cosolvent.

According to another aspect of the present invention, there is provided a pharmaceutical aerosol formulation wherein the propellant is selected from the group consisting of 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro - n-propane and mixtures thereof.

The formulations of the invention may be buffered by the addition of a suitable buffer.

Capsules and columns of, for example, gelatin for use in an inhaler or insufflator may be formulated with a powder mixture containing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a suitable powder base such as lactose or starch. Inhalation. Each capsule or column may generally contain from 200 μg to 10 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, a compound of formula (I) or a pharmaceutically acceptable salt thereof can be presented without an excipient such as lactose.

The proportion of the active compound of the formula (I) or a pharmaceutically acceptable salt thereof in the topical composition of the invention may depend on the exact type of formulation to be prepared, but will generally range from 0.01% to 10% by weight. Inside. Usually, for most types of preparations, the proportion used It will be in the range of 0.05% to 1%, for example 0.1% to 0.5%.

The aerosol formulation is preferably arranged such that each metered dose or "puff" of the aerosol contains from 20 μg to 10 mg, preferably from 20 μg to 5 mg, more preferably from about 20 μg to 0.5 mg of the compound of formula (I). Administration can be once daily or several times daily, for example 2, 3, 4 or 8 times, for example, 1, 2 or 3 doses per administration. The total daily dose to the aerosol will range from 100 μg to 10 mg, for example from 200 μg to 5 mg. The total daily dose and metered dose delivered by the capsule and column in the inhaler or insufflator will typically be doubled by delivery with the aerosol formulation.

In the case of a suspension aerosol formulation, the particle size of the particulate (eg, micronized) drug should, for example, allow substantially all of the drug to be inhaled into the lungs upon administration of the aerosol formulation and will therefore be less than 100 microns, which is desirable The ground is less than 20 microns, and specifically in the range of 1 micron to 10 microns, such as 1 micron to 5 microns, more preferably 2 microns to 3 microns.

The formulations of the present invention can be prepared, for example, by dispersing or dissolving a pharmaceutical agent and a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a selected propellant, in an appropriate container, by means of an ultrasonic treatment or a high shear mixer. . The process is desirably carried out under controlled humidity conditions.

The chemical and physical stability and pharmaceutical acceptability of the aerosol formulations of the present invention can be determined by techniques well known to those skilled in the art. Thus, for example, the chemical stability of the components can be determined by HPLC analysis, for example, after long-term storage of the product. Physical stability data can be obtained from other conventional analytical techniques (eg, by leak testing, by valve delivery analysis (average injection weight per actuation), by reproducibility analysis (active ingredient per actuation) and spray distribution analysis) .

The stability of the suspended aerosol formulation of the present invention can be measured by conventional techniques (e.g., by measuring the flocculation size distribution using a backscattering instrument or by cascading collisions or by "twin impinger" analysis methods. Particle size distribution) to measure. As used herein, reference to "double collision" analysis means "determination of deposition of the emitted dose in pressurized inhalation using device A", as in British Pharmacopaeia 1988, pages A204-207, appendix As defined in XVII C. These techniques enable the calculation of the "absorbable portion" of the aerosol formulation. A method for calculating the "absorbable portion" is by referring to the "fine particle portion", which is the amount of active ingredient collected in the lower collision chamber each time, expressed as the above-mentioned double collision method for each start-up delivery. The percentage of the total active ingredient.

The term "metered dose inhaler" or MDI means a unit comprising a tub, a fastening cap covering the tub and a dispensing metering valve located in the lid. The MDI system includes suitable multiplexing devices. Suitable multiplex devices include, for example, valve actuators and cylindrical or conical channels through which the medicament can be delivered from the canister to the nose or mouth of the patient via a metering valve, such as a nozzle actuator.

MDI cans typically contain a container that is resistant to the propellant used, such as a plastic or plastic coated glass bottle or preferably a metal can, such as aluminum or an alloy thereof, which may optionally be anodized, lacquered, and/or plastic coated. (For example, WO 96/32099 is incorporated herein by reference, in which part or all of the inner surface is coated with one or more fluorocarbon polymers, optionally in combination with one or more non-fluorocarbon polymers) The container is sealed by a metering valve. The barrel can be fastened by ultrasonic welding, screwing or crimping. The MDI taught herein can be prepared by methods known in the art (see, for example, Byron, supra and WO 96/32099). Preferably, the canister is equipped with a bucket assembly in which the drug metering valve is located in the lid and the lid is crimped in place.

In one embodiment of the invention, the metal inner surface of the barrel is coated with a fluoropolymer (more preferably blended with a non-fluoropolymer). In another embodiment of the invention, the metal inner surface of the barrel is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyether oxime (PES). In yet another embodiment of the invention, the entire metal inner surface of the barrel is coated with a polymer blend of polytetrafluoroethylene (PTFE) and polyether oxime (PES).

The metering valve is designed to deliver a metered amount of formulation per actuation and to incorporate a gasket to prevent propellant leakage through the valve. The gasket may comprise any suitable elastomeric material such as low density polyethylene, chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrile rubber, butyl rubber and neoprene. Suitable valves are commercially available from well-known manufacturers in the aerosol industry, such as from Valois, France (e.g., DF10, DF30, DF60), Bespak plc, UK (e.g., BK300, BK357), and 3M-Neotechnic Ltd, UK (e.g., SpraymiserTM ^). ).

In various embodiments, the MDI can also be combined with other structures (such as, but not limited to, packaging for storing and containing MDI, including those described in U.S. Patent Nos. 6,119,853, 6,179,118, 6,315,112, 6,352,152, 6,390,291 And the use of a dose counter unit (such as, but not limited to, those described in U.S. Patent Nos. 6,360,739 and 6,431,168).

Conventional bulk manufacturing methods and machines well known to those skilled in the art for the manufacture of pharmaceutical aerosols can be used to prepare large scale batches for commercial production of filled cans. Thus, for example, in a large volume manufacturing process for preparing a suspended aerosol formulation, a metering valve is crimped onto an aluminum drum to form an empty can. The particulate medicament is added to the filling vessel and the liquefied propellant is pressure filled into the manufacturing vessel along with the optional excipients through the filling vessel. The drug suspension is mixed prior to circulation to the filling machine and an aliquot of the drug suspension is then filled into the can through a metering valve. In an exemplary high volume manufacturing process for preparing a solution aerosol formulation, a metering valve is crimped onto an aluminum drum to form an empty can. The liquefied propellant, along with optional excipients and dissolved medicament, is pressure filled into the manufacturing vessel through a filling vessel.

In an alternative method, an aliquot of the liquefaction formulation is added to the open canister under conditions sufficient to ensure that the formulation does not vaporize, and then the metering valve is crimped onto the can.

Typically, in preparing batches for pharmaceutical use, each canister is inspected for weighing, coded with a lot number and filled into a pan for storage prior to release testing.

Suspensions and solutions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered to a patient via a nebulizer. The solvent or suspending agent for atomization may be any pharmaceutically acceptable liquid such as water, aqueous saline, alcohol or glycol (eg, ethanol, isopropyl alcohol, glycerol, propylene glycol, polyethylene glycol, etc.) or mixture. The saline solution employs a salt which exhibits little or no pharmacological activity after administration. Organic salt (such as alkali metal or ammonium halogen) Salts such as sodium chloride, potassium chloride or organic salts such as potassium, sodium and ammonium salts or organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid and the like can be used for this purpose.

Other pharmaceutically acceptable excipients can be added to the suspension or solution. By adding inorganic acids (such as hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid), organic acids (such as ascorbic acid, citric acid, acetic acid and tartaric acid, etc.), complexing agents (such as EDTA or citric acid and its salts) or antioxidants ( For example, an antioxidant such as vitamin E or ascorbic acid is used to stabilize the compound of formula (I) or a pharmaceutically acceptable salt thereof. These materials may be used alone or together to stabilize the compound of formula (I) or a pharmaceutically acceptable salt thereof. Preservatives such as benzalkonium chloride or benzoic acid and salts thereof may be added. Surfactants may especially be added to improve the physical stability of the suspension. Such surfactants include lecithin, disodium dioctylsulfosuccinate, oleic acid, and sorbitan ester.

In yet another aspect, the invention pertains to dosage forms suitable for intranasal administration.

Formulations for administration to the nose can include a pressurized aerosol formulation and an aqueous formulation for administration to the nose by a pressurized pump. Formulations that are not pressurized and are suitable for topical administration to the nasal cavity are of particular interest. For this purpose, suitable formulations contain water as a diluent or carrier. Aqueous formulations for administration to the lungs or nose can be provided with conventional excipients such as buffers, tonicity modifiers and the like. Aqueous formulations can also be administered to the nose by nebulization.

The compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated for use in a self-fluid dispenser (e.g., a fluid dispenser having a dispensing nozzle or dispensing orifice, applied by a user to a pumping mechanism of the fluid dispenser) The fluid formulation delivered by the metered dose of the fluid formulation is dispensed via the dispensing nozzle or dispensing orifice. The fluid dispensers are typically provided with a reservoir having a plurality of metered fluid formulation doses that are dispensed when the sequential pump is activated. The dispensing nozzle or orifice can be configured to be inserted into the user's nostrils to dispense a fluid formulation spray into the nasal cavity. A fluid dispenser of the type described above is illustrated and explained in WO 05/044354, the entire contents of which is incorporated herein by reference. The dispenser has a housing containing a fluid discharge device, the fluid discharge device having a fluid accommodation The compression pump on the container of the compound. The outer casing has at least one finger operable side bar movable inwardly relative to the outer casing to cam the container upwardly in the outer casing such that the pump compresses the metered dose of the formulation and passes through the nasal nozzle of the outer casing Pump it out of the pump handle. In one embodiment, the fluid dispenser is of the general type illustrated in Figures 30-40 of WO 05/044354.

A pharmaceutical composition suitable for intranasal administration (wherein the carrier is a solid) comprises a coarse powder having a particle size in the range of, for example, 20 micrometers to 500 micrometers, which is a powder-containing container which is maintained close to the nose by the nasal cavity. Inhale quickly to give. A suitable composition for administration in the form of a nasal spray or in the form of a nasal drop, wherein the carrier is a liquid, comprises an aqueous or oily solution of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions suitable for transdermal administration can be presented as discrete patches intended to maintain long-term intimate contact with the epidermis of the patient. For example, the active ingredient can be delivered from the patch by iontophoresis as outlined in Pharmaceutical Research, 3(6), 318 (1986).

The pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For example, ointments, creams and gels can be formulated with aqueous or oily bases with the addition of suitable thickening and/or gelling agents and/or solvents. Thus, such matrices may, for example, include water and/or oil (eg, liquid paraffin or vegetable oils such as peanut oil or castor oil) or solvents (eg, polyethylene glycol). Thickeners and gelling agents which may be used depending on the nature of the substrate include soft paraffin, aluminum stearate, cetearyl alcohol, polyethylene glycol, lanolin, beeswax, carboxypolymethylene and cellulose derivatives, And / or glyceryl monostearate and / or nonionic emulsifier.

Lotions may be formulated with aqueous or oily bases and usually contain one or more emulsifiers, stabilizers, dispersing agents, suspending agents or thickening agents.

Powders for external application can be formed by any suitable powder base such as talc, lactose or starch. Drops can also be used to also contain one or more dispersants, solubilizers, suspensions An aqueous or non-aqueous base of the agent or preservative is formulated.

Topical formulations can be administered by applying one or more times per day to the affected area. On the area of the skin, a closed dressing can advantageously be used. Continuous or long-term delivery can be achieved by an adhesive reservoir system.

For the treatment of ocular nitriles or other external tissues such as the mouth and skin, the compositions may be applied as a topical ointment or cream. When formulated in an ointment, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used with a paraffinic or water miscible ointment base. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents, and solutes which render the formulation isotonic with the blood of the intended recipient; And non-aqueous sterile suspensions, which may include suspending agents and thickening agents. The compositions can be presented in unit dose or multi-dose containers (eg, sealed ampoules and vials) and can be stored under lyophilized (lyophilized) conditions, with the addition of a sterile liquid carrier (eg, water for injection) just prior to use. . The injectable solutions and suspensions can be prepared from sterile powders, granules and tablets.

The invention will now be illustrated by the following non-limiting examples.

General method

Starting materials are commercially available unless otherwise stated. All solvents and commercially available reagents are laboratory grade and are used as received.

If a non-image isomer is indicated and only relative stereochemistry is mentioned, a bold or cut entity key symbol is used ( /''''''). If absolute stereochemistry is known and the compound is a single mirror image isomer, if appropriate, use a bold or cut wedge symbol ( /'''''').

Analytical method

Method A

LCMS was applied to an Acquity UPLC BEH C ₁₈ column (50 mm × 2.1 mm id 1.7 μm packing diameter) at 40 ° C using 10 mM ammonium bicarbonate in water with the following elution gradient (solvent using ammonia solution (solvent A) and Acetonitrile (solvent B) was adjusted to pH 10) to carry out the dissolution: 0-1.5 min: 1-97% B, 1.5-1.9 min: 97% B, 1.9-2.0 min: 100% B, flow rate 1 mL/min. The UV detection is a total signal from a wavelength of 210 nm to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating scan positive and negative electrospray. The ionized data is rounded to the nearest integer.

Method B

LCMS was applied to an Acquity UPLC BEH C ₁₈ column (50 mm x 2.1 mm id 1.7 μm packing diameter) at 40 ° C using a 0.1% v/v solution of formic acid in water (solvent A) using the following elution gradient. The formic acid was dissolved in 0.1% v/v solution in acetonitrile (solvent B) to perform: 0-1.5 min: 3-100% B, 1.5-1.9 min: 100% B, 1.9-2.0 min: 3% B, flow rate It is 1 mL/min. The UV detection is a total signal from a wavelength of 210 nm to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating scan positive and negative electrospray. The ionized data is rounded to the nearest integer.

Method C

LCMS based on the Acquity UPLC BEH C ₁₈ column (50mm × 2.1mm id1.7μm packed in diameter) at 40 ℃ on, using the following elution gradient with trifluoroacetic acid in water (solvent A), of 0.1% v / v The solution and trifluoroacetic acid were dissolved in 0.1% v/v solution in acetonitrile (solvent B) to perform: 0-1.5 min: 3-100% B, 1.5-1.9 min: 100% B, 1.9-2.0 min: 3 % B, flow rate is 1 mL/min. The UV detection is a total signal from a wavelength of 210 nm to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating scan positive and negative electrospray. The ionized data is rounded to the nearest integer.

Method D

LCMS was applied to a HALO C ₁₈ column (50 mm × 4.6 mm id 2.7 μm packing diameter) at 40 ° C using a 0.1% v/v solution of formic acid in water (solvent A) and formic acid on the following elution gradient. The 0.1% v/v solution in acetonitrile (solvent B) was dissolved to perform: 0-1 min: 5% B, 1-1.01 min: 95% B, 2.01-2.5 min: 5% B, flow rate 1.8 mL/min . UV detection is the total signal at the following wavelengths: 214 nm and 254 nm. MS: ion source: ESI; drying gas flow rate: 10 L/min; nebulizer pressure: 45 psi; drying gas temperature: 330 ° C; capillary voltage: 4000 V.

Method E

LCMS was applied to a HALO C ₁₈ column (50 mm × 4.6 mm id 2.7 μm packing diameter) at 40 ° C using a 0.1% v/v solution of formic acid in water (solvent A) and formic acid on the following elution gradient. The 0.1% v/v solution in acetonitrile (solvent B) was dissolved to perform: 0-1.8 min: 5% B, 1.8-2.01 min: 100% B, 2.01-2.8 min: 5% B, flow rate 1.5 mL/ Min. UV detection is the total signal at the following wavelengths: 214 nm and 254 nm. MS: ion source: ESI; detector voltage: 1.4 KV; hot block temperature: 250 ° C; CDL temperature: 250 ° C; nebulizer gas flow rate: 1.5 mL/min.

General GCMS method

GCMS was performed on an Agilent 6890/5973 GCMS apparatus with an Agilent capillary column HP-5 (0.25 [mu]m x 30 m, i.d. 0.25 mm). The initial temperature is 50 °C. The equilibrium time is 0.50 min. The initial time is 1.00 min. The temperature was then increased to 180 ° C at a rate of 10 ° / min, then increased to 240 ° C at a rate of 20 ° C / min, followed by 5.00 min at 240 ° C. The injection mode is splitless. The gas flow rate was 1.00 mL/min and the total flow rate was 23.2 mL/min. The average speed is 36 cm/sec. Get mode scan. The ionization method is 70 eV EI (electron ionization).

Using Bruker DPX 400MHz reference tetramethyl silane-recording ¹ H NMR spectrum.

The ruthenium dioxide chromatography technique includes automated (Flashmaster, Biotage SP4) technology or manual chromatography on pre-packed columns (SPE) or manually packed flash column.

When the name of a commercial supplier is given after the name of the compound or reagent (eg "Compound X (Aldrich)" or "Compound X/Aldrich"), this means that Compound X can be from a commercial supplier (eg named commercial supplier) )obtain.

Similarly, when a literature or patent reference (e.g., "Compound Y (EP 0 123 456)") is given after the name of the compound, this means that the preparation of the compound is set forth in the referenced reference.

The names of the intermediates and examples have been obtained using the compound naming program in ChemBioDraw Ultra v12 or alternatively using "ACD Name Pro 6.02".

General MDAP purification method

The quality-guided automated preparative chromatography (MDAP) method that has been or can be used for compound purification is listed below.

MDAP (Method A). HPLC analysis was carried out on an XBridge C18 column (100 mm x 30 mm id 5 μm packed diameter) at ambient temperature with 10 mM ammonium bicarbonate in water (using ammonia solution (solvent A) and acetonitrile (solvent B). Adjusting to pH 10) The dissolution is carried out using a gradient of the dissolution between 0% and 100% solvent B over 15 or 25 minutes.

The UV detection is an average signal from a wavelength of 210 nm to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating scan positive and negative electrospray. The ionized data is rounded to the nearest integer.

MDAP (Method B). HPLC analysis was carried out at ambient temperature on a Sunfire C18 column (150 mm x 30 mm id 5 μm packed diameter), 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B). The dissolution was carried out using a dissolution gradient between 0% and 100% solvent B in 15 or 25 minutes.

The UV detection is an average signal from a wavelength of 210 nm to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating scan positive and negative electrospray. The ionized data is rounded to the nearest integer.

MDAP (Method C). HPLC analysis was performed on a Sunfire C18 column (150 mm x 30 mm id 5 μm packed diameter) at ambient temperature with 0.1% v/v solution of trifluoroacetic acid in water (solvent A) and trifluoro The 0.1% v/v solution of acetic acid in acetonitrile (solvent B) was eluted using a elution gradient between 0% and 100% solvent B over 15 or 25 minutes.

The UV detection is an average signal from a wavelength of 210 nm to 350 nm. Mass spectra were recorded on a Waters ZQ mass spectrometer using alternating scan positive and negative electrospray. The ionized data is rounded to the nearest integer.

General chiral HPLC method

Method A: Chiral analytical chromatography

Method B: Chiral preparative chromatography

Method C: Chiral preparative chromatography

Initial situation:

The leading edge of the peak is initially cut out using the initial conditions. This enrichment cuts out the desired first isomer of the isolate, which is then further purified using minor conditions.

Secondary condition:

Chiral (analytical) HPLC method D:

Analytical chiral HPLC spectra were recorded on a standard Agilent 1100 Series HPLC system using a DAD UV detector equipped with a 25 cm x 0.46 cm Chiralpak IC column [ICOOCE-OG022], which was used at rt at a rate of 1 mL/min. 60% isopropanol / heptane was eluted and analyzed at a wavelength of 215 nm.

Chiral (preparative) HPLC method E:

Approximately 110 mg of the racemate was dissolved in IPA (2 mL) and heptane (1 mL). Injection; 1.5 mL of the above sample solution was injected onto a column (2 cm x 25 cm Chiralpak IC lot number IC00CJ-LG008), and eluted with 50% IPA/heptane at a rate of 20 mL/min and analyzed at a wavelength of 215 nm.

Chiral (preparative) HPLC method F:

Approximately 95 mg of the racemate was dissolved in EtOH (3 mL) and heptane (2 mL). Injection; 1 mL of the above sample solution was injected onto a column (2 cm × 25 cm Chiralpak IC batch number IC00CJ-LG008), and eluted with 30% EtOH/heptane at a rate of 20 mL/min. Analysis at a wavelength of 215 nm.

Chiral (preparative) HPLC method G:

Approximately 100 mg of the racemate was dissolved in EtOH (1 mL) and heptane (1 mL). Injection; 2 mL of the above sample solution was injected onto a column (30 mm x 25 cm Chiralpak IC lot number IC10028-01), and eluted with 20% EtOH/heptane at a rate of 30 mL/min and analyzed at a wavelength of 215 nm.

Chiral (preparative) HPLC method H1:

Approximately 100 mg of the racemate was dissolved in EtOH (1 mL) and heptane (1 mL). Injection; 2 mL of the above sample solution was injected onto a column (2 cm x 25 cm Chiralpak IC lot number IC00CJ-LG008), and eluted with 30% EtOH/heptane at a rate of 20 mL/min and analyzed at a wavelength of 215 nm. A total of 8 injections. Partial collection: The fraction from 21.5 min to 23 min was mixed and labeled as peak 1. The fraction from 23.5 min to 26.5 min was mixed and labeled as peak 2. The fraction from 27 min to 31 min was mixed and labeled as peak 3. The mixed fraction was then concentrated in vacuo using a rotary evaporator and transferred to a weigh flask for final analysis as described by analytical method (H1) below

Peak 1 (36mg)

Peak 2 (272mg)

Peak 3 (209mg)

Analytical HPLC method H1:

Approximately 0.5 mg of the sample was dissolved in 50% EtOH / heptane (1 mL). Injection; 20 μL of the above sample solution was injected onto a column (4.6 mm × 25 cm Chiralpak IC Lot No. IC00CE-LI045), and eluted with 50% EtOH/heptane at a rate of 1 mL/min and analyzed at a wavelength of 215 nm.

Peak 2 (272 mg) is known to contain two compounds. A second analysis and preparation method was developed to separate the two compounds (see below).

Analytical HPLC method H2:

Approximately 0.5 mg of the sample was dissolved in 50% IPA/heptane (1 mL). Injection; 20 μL of the above sample solution was injected onto a column (4.6 mm × 25 cm Chiralpak IC batch No. AD00CE-KF099), and eluted with 25% IPA/heptane at a rate of 1 mL/min and analyzed at a wavelength of 215 nm.

Preparative HPLC method H2:

Approximately 100 mg of the racemate was dissolved in IPA (1 mL) and heptane (1 mL). Injection; 2 mL of the above sample solution was injected onto a column (2 cm x 25 cm Chiralpak AD lot No. AD00CJ-JA001), and eluted with 20% IPA/heptane at a rate of 20 mL/min and analyzed at a wavelength of 215 nm. A total of 3 injections. Partial collection: Part from 12 min to 16 min was mixed and labeled as peak 1. The fraction from 18 min to 30 min was mixed and labeled as peak 2. The mixed fractions were then concentrated in vacuo using a rotary evaporator and transferred to a weighed flask for final analysis as described by analytical HPLC method (H2) above.

Peak 1 (28mg)

Peak 2 (239 mg) - Peak 2 is expected to be an image isomer and continue to be used

Chiral (preparative) HPLC method I:

Approximately 24 mg of the racemate was dissolved in EtOH (2 mL) and heptane (2 mL). Injection; 4 mL of the above sample solution was injected onto a column (30 mm × 25 cm Chiralpak ADH (5um) batch No. ADH10029-01), and eluted with 80% EtOH/heptane at a rate of 30 mL/min and analyzed at a wavelength of 215 nm. .

Chiral (preparative) HPLC method J:

Approximately 80 mg of the racemate was dissolved in EtOH (4 mL) + isopropylamine (1 mL) and heptane (3 mL). Injection; 0.25 mL of the above sample solution was injected onto a column (2 cm × 25 cm Chiralpak IB batch No. IB00CJ-KD002), and eluted with 10% EtOH (+0.2% isopropylamine) / heptane at a rate of 20 mL / min and Analysis at a wavelength of 215 nm. The total number of injections = 25.

Chiral (preparative) HPLC method K:

The sample (275 mg) was dissolved in IPA. Subsequently, 0.4-0.5 mL was manually injected into a column (2 cm × 25 cm Chiralpak IA (5 um)) using a 1 mL plastic syringe, and eluted with 25% IPA (+0.2% isopropylamine) / hexane at a rate of 20 mL/min. The analysis was carried out on a UV DAD at a wavelength of 300 nm (bandwidth 180 nm, reference 550 nm (bandwidth 100 nm)).

Chiral (preparative) HPLC method L:

A sample (183 mg) was dissolved in EtOH. Subsequently, 0.75 mL was manually injected into a column (2 cm × 25 cm Chiralpak IC (5 um)) using a 1 mL plastic syringe, and eluted with 100% EtOH (+0.2% isopropylamine) at a rate of 15 mL/min and on UV DAD. The wavelength of 300 nm (bandwidth 180 nm, reference 550 nm (bandwidth 100 nm), also 218 nm and 280 nm (no reference)). A portion of the combined solution was evaporated to dryness using a rotary evaporator. A chiral analysis of Part 2 indicated the presence of 5% isomer 1 . Therefore, the sample was re-chromatized using the same system (about 40 mg in 4 mL, 0.5 mL injection) and the fraction corresponding to the second eluting isomer in the analysis was pooled and concentrated as above.

Chiral (preparative) HPLC method M:

A sample (40 mg) was dissolved in EtOH (about 4 mL). Subsequently, 0.5 mL (+0.1 mL of isopropylamine) was manually injected into a column (2 cm × 25 cm Chiralpak IA (5 μm)) using a 1 mL plastic syringe, and eluted with 30% EtOH (+0.2% isopropylamine) / heptane at a rate. It was 45 mL/min and analyzed on a UV DAD at a wavelength of 300 nm (bandwidth 180 nm, reference 550 nm (bandwidth 100 nm)). A portion of the combined solution was evaporated to dryness using a rotary evaporator. A chiral analysis of Part 2 indicated the presence of 5% isomer 1 . Therefore, this sample was re-chromatized using the following conditions: 0.45 mL of the sample was diluted with 0.45 mL of hexane and 100 uL of isopropylamine was added. This material was injected onto a column (2 cm x 25 cm Chiralpak IA (5 um)) using a 1 ml glass syringe and eluted with 30% -> 50% EtOH (+ 0.2% isopropylamine) / heptane at a rate of 45 mL / min and The analysis was carried out on a UV DAD at a wavelength of 300 nm (bandwidth 180 nm, reference 550 nm (bandwidth 100 nm)).

Chiral (preparative) HPLC method N:

Approximately 110 mg of the racemate was dissolved in EtOH (1 mL) and heptane (1 mL). Injection; 1 mL of the above sample solution was injected onto a column (30 mm × 25 cm Chiralpak ADH (5um) batch No. ADH10029-01), and eluted with 25% EtOH/heptane at a rate of 40 mL/min and analyzed at a wavelength of 215 nm. . The total number of injections = 2.

Intermediate 1: 1-Ethyl-7-methyl-1H-indole

7-Methylindole (2.0 g, 15.25 mmol, available from, for example, Apollo Scientific) in anhydrous DMF (20 mL) was treated with sodium hydride (60% in mineral oil, 0.67 g, 16.75 mmol). The mixture was stirred at ambient temperature under nitrogen for ca. 2 min then treated with ethyl iodide (1.34 mL, 16.75 mmol). The reaction was stirred at ambient temperature under nitrogen for ca. 4.5 h, diluted with water andEtOAc. The combined DCM extracts were dried (hydrophobic glass), reduced to dryness in vacuo and further dried under vacuum at 55 ° C to yield 1-ethyl-7-methyl-1H-indole as a brown oil. (2.47g).

^{1 H NMR (400MHz) :( DMSO} -d6): δH 7.35 (1H, d), 7.29 (1H, d), 6.89-6.83 (2H, m), 6.40 (1H, d), 4.38 (2H, q) , 2.68 (3H, s), 1.33 (3H, t).

Intermediate 2: 1-Ethyl-5-methyl-1H-indole

Prepared from 5-methylindole (available, for example, from Lancaster Synthesis Ltd.) in a similar manner to Intermediate 1.

^{1 H NMR (DMSO-d6)} : δH 7.35-7.30 (3H, m), 6.95 (1H, d), 6.31 (1H, d0,4.16 (2H, q), 2.37 (3H, s), 1.33 (3H, t)

Intermediate 3: 1-Ethyl-4-methyl-1H-indole

Prepared from 4-methylindole (available from, for example, Chondtech Inc.) in a manner similar to Intermediate 1.

¹ H NMR (DMSO-d6): δH 7.35 (1H, d), 7.27 (1H, d), 7.02 (1H, t), 6.81 (1H, d), 6.44 (1H, d), 4.18 (2H, q) ), 2.45 (3H, s), 1.34 (3H, t).

Intermediate 4: 3,4-Dihydro-2 H -[1,4]oxazepine[2,3,4- hi ]吲哚

7-(3-Chloropropoxy)-1 H -indole (2.71 g, 12.9 mmol, prepared for this intermediate has been reported in US Pat. No. 1998/5776963 A) in DMF over 10 min. Sodium hydride (60% suspension in mineral oil, 1.03 g, 25.8 mmol) was added portionwise to a solution (25 mL). The reaction mixture was warmed to rt over 1 h then cooled again with ice water then EtOAc (1N, 25 <RTIgt;

The mixture was partitioned with EtOAc (EtOAc)EtOAc. The combined organic layers were dried with MgSO ₄ and then evaporated. The crude material was purified with EtOAc EtOAcjjjjjj

LCMS (Method A): Rt = 1.05 min, MH+ = 174.0.

Intermediate 5: 1-Ethyl-1 H -indole-2-carbaldehyde

To a flask of potassium hydroxide (2.84 g, 50.6 mmol) was added dimethyl sulfonium (DMSO) (91 mL) and the mixture was stirred at rt for 10 min. To the reaction mixture was added 1H-indole-2-carbaldehyde (2.04 g, 14.05 mmol, e.g. from Sigma-Aldrich) and stirred at rt under nitrogen for 1 h. Ethyl bromide (1.795 mL, 23.89 mmol) was added dropwise and the~~~~~~ The reaction was quenched by careful addition of water (100 mL). Et ₂ O (100 mL) was added and the layers were separated. With Et ₂ O ₍₂ × 100mL) and the aqueous layer was extracted further washed with water (2 × 50mL) The combined organics were back-extracted. The organic layer was then dried (Na ₂ SO ₄₎ and concentrated in vacuo to afford a brown oily crude product. The crude product was purified on EtOAc (EtOAc)EtOAc. The appropriate portions were combined and evaporated in vacuo tolulujjjjjjjjjjjjjjjjjjjjjjjj

LCMS (Method B): Rt = 1.08 min, MH ⁺ = 174.0

Other intermediate systems indicated in the table below were prepared in a manner similar to Intermediate 5:

Intermediate 11: 1-Ethyl-7-methyl-1H-indole-2-carbaldehyde

A solution of 1-ethyl-7-methyl-1H-indole (1.5 g, 9.42 mmol) in dry THF (15 mL) A solution of n-butyllithium (1.6 M in hexanes, 7.4 mL, 11.84 mmol) was added dropwise over about 10 min. After the addition of n-butyllithium, the reaction was stirred for about 2 min, then the ice/salt bath was removed, allowed to warm to ambient temperature and stirred at ambient temperature under nitrogen for 1.5 h. The reaction was cooled and approximately 2min added DMF (5mL) the cold solution in CO ₂ / acetone bath. The reaction was stirred at -78.degree. C. under nitrogen for additional 2.5 h then quenched with aqueous saturated sodium bicarbonate and warmed to ambient temperature for one week. The reaction was diluted with water and extracted with DCM (×2). The combined DCM extracts were dried (hydrophobic glass) and reduced to dryness in vacuo to yield a yellow oil. The residue was dissolved in cyclohexane and applied to a ruthenium dioxide column (10 g). The column was eluted with a gradient of ethyl acetate / cyclohexane (0-10%). Appropriate fractions were combined and reduced to dryness in vacuo to give 1-ethyl-7-methyl-1H-indole-2-carbaldehyde (0.97 g) as a pale yellow oil.

LCMS (Method ^{B): Rt 1.15min, MH +} 188.

Intermediate 12: 1-Ethyl-5-methyl-1H-indole-2-carbaldehyde

Prepared from 1-ethyl-5-methyl-1H-indole in a similar manner to intermediate 11.

¹ H NMR (DMSO-d6): δH 9.88 (1H, s), 7.55 (2H, m), 7.38 (1H, s), 7.27 (1H, dd), 4.56 (2H, q), 2.41 (3H, s ), 1.26 (3H, t)

Intermediate 13: 1-Ethyl-4-methyl-1H-indole-2-carbaldehyde

Prepared from 1-ethyl-4-methyl-1H-indole in a similar manner to intermediate 12.

¹ H NMR (DMSO-d6): δH 9.91 (1H, s), 7.54 (1H, s), 7.47 (1H, d), 7.33 (1H, t), 6.98 (1H, d), 4.58 (2H, q) ), 2.55 (3H, s), 1.27 (3H, t).

Intermediate 14: 1-Ethyl-6-methyl-1H-indole-2-carbaldehyde

Prepared from 1-ethyl-6-methyl-1H-indole in a similar manner to intermediate 12.

LCMS (Method B): Rt = 1.17 min, MH ⁺ = 188.0

The other intermediate systems in the table below were prepared in a manner similar to Intermediate 11:

General method for the alkylation of hydrazine in DMF using K ₂ CO ₃ and optionally Substituting ArCH ₂ X (where X-based halo):

Add to a suspension of 1H-indole-2-carbaldehyde (1 eq.) and potassium carbonate (1 eq.) in N,N-dimethylformamide (DMF) (1.7 M) at rt. A suitable benzyl halide (1 equivalent). The reaction mixture was heated to 100 ° C to 110 ° C and stirred for 2-20 h. The reaction was then stopped and quenched by the addition of water. The organics were extracted into EtOAc or Et ₂ O (3 ×) and the combined the organics were washed with water, dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product. The crude product was purified on EtOAc using EtOAc/EtOAc EtOAc. The appropriate fractions are combined and evaporated under vacuum to yield the desired product.

The following compounds were prepared by this method:

Intermediate 27: 1-(cyclopropylmethyl)-5-(methyloxy)-1 H -indole-2-carbaldehyde

To a flask containing sodium hydride (121.1 mg, 3.03 mmol) was added 5-(methyloxy)-1H-indole-2-carbaldehyde (489.1 mg, 2.79 mmol, available from, for example, Fluorochem) to N,N- A solution of methylformamide (DMF) (12 mL) was stirred at rt under nitrogen. After 20 min, (bromomethyl)cyclopropane (0.35 mL, 3.61 mmol) was added portionwise. The reaction was stirred at 0&lt;0&gt;C for 20 min then warmed to rt and stirred overnight (16h). The reaction mixture was quenched by the addition of water (50 mL). Et ₂ O (50 mL) was added and the layers were separated. The aqueous layer was further extracted with Et ₂ O (2×50 mL). LCMS color development of the aqueous mixture left some product. The organics were further extracted and the combined aqueous layer was washed with water (3 × 50mL) with Et ₂ O ₍₂ × 60mL) was back extracted. The organic phase was dried over Na ₂ SO _4, passed through a hydrophobic frit and concentrated in vacuo to yield a brown oil. The crude product was purified on cerium oxide (25 g). The column was chromatographed using a gradient of 0-50% ethyl acetate / cyclohexane. The appropriate portion and concentrated in vacuo to yield a brown oil 1- (cyclopropylmethyl) -5- (methyloxy) -1 H - indole-2-carbaldehyde (555mg, 87%).

LCMS (Method B): Rt = 1.14 min, MH ⁺ = 230.1

Other examples indicated in the table below were prepared in a manner similar to Intermediate 27.

Intermediate 37: 1-[(1-Methyl-1 H -pyrazol-4-yl)methyl]-1 H -indole-2-carbaldehyde

To a flask containing sodium hydride (280 mg, 7.00 mmol) was added 1H-indole-2-carbaldehyde (504 mg, 3.47 mmol, available from, for example, Sigma-Aldrich) to N,N-dimethylformamide (DMF) ( The solution in 12 mL) was stirred at rt under nitrogen for 1.5 h. Dissolve 4-(bromomethyl)-1-methyl-1H-pyrazole (607.8 mg, 3.47 mmol) in N,N-dimethylformamide (DMF) (2 mL), then at 0 ° C It was added portionwise to the reaction mixture and stirred under nitrogen for 1 h. The reaction mixture was brought to rt and stirred under nitrogen (18 h). Additional 4-(bromomethyl)-1-methyl-1H-pyrazole (598.5 mg, 3.42 mmol) in N,N-dimethylformamide (DMF) (2 mL) Stir under rt for 4 h. By the addition of water (50mL) was added and the reaction mixture was quenched with Et ₂ O (50mL) and the layers separated. The aqueous layer was further extracted with Et ₂ O (3 × 50mL) and the combined organics were back extracted with _{H 2 O (2 × 50mL)} . The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude product was purified on cerium oxide (50 g). The column was eluted using a gradient of 15-100% ethyl acetate / cyclohexane. The appropriate portions and concentrated to afford the desired product as a brown oily 1 - [(1-methyl -1 H - pyrazol-4-yl) methyl] -1 H - indole-2-carbaldehyde (1.27 g of, 65%).

LCMS (Method B): Rt = 0.90 min, MH ⁺ = 240.0

Intermediate 38: 1-(4-Pyridylmethyl)-1H-indole-2-carbaldehyde

To a suspension of sodium hydride (0.716 g, 17.91 mmol) in tetrahydrofuran (THF) (8.00 mL), EtOAc (1 g, 6. A solution of Aldrich in N,N-dimethylformamide (DMF) (16 mL). After 1 h, 4-chloromethylpyridine hydrochloride (1.356 g, 8.27 mmol) was added portionwise. The reaction was stirred at 0 &lt;0&gt;C for 1 h and then allowed to warm to rt and stirred 16 h. The reaction was allowed to stand without stirring for 24 h and then quenched by the addition of water (100 mL). Et ₂ O (100 mL) was added and the layers were separated. With Et ₂ O ₍₂ × 50mL) and the aqueous layer was further extracted with the combined organics were back extracted with _{H 2 O (2 × 30mL)} . The organic phase was dried (Na ₂ SO ₄₎ and concentrated in vacuo to afford a brown oily crude product. The crude product was purified on a pad of EtOAc (EtOAc:EtOAc:EtOAc Appropriate fractions were combined and evaporated <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

LCMS (Method B): Rt = 0.61 min, MH ⁺ = 237.1

Other intermediate systems indicated in the table below were prepared in a manner similar to Intermediate 38:

Intermediate 41: 1-(2-Hydroxyethyl)-1 H -indole-2-carbaldehyde

1,3-dioxolan-2-one (97 mg, 1.009 mmol), 1H-indole-2-carbaldehyde (145 mg, 0.999 mmol, available from, for example, Sigma-Aldrich) and sodium hydroxide (4.00 mg, 0.100) Ment) (from pellet milling) a solution of N,N-dimethylformamide (DMF) (1 mL) was heated to 140 ° C for 16 h. The reaction was cooled, and by the addition of water (30mL) and Et ₂ O (30mL) quenched. The layers were separated and the aqueous layer was extracted with Et ₂ O (2×30 mL). The combined organics were washed with water (2 × 30mL) and then back-extracted dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product as a black oil. The crude product was purified on a pad of EtOAc (25 g) using EtOAc EtOAc. Appropriate fractions were combined and evaporated in vacuo to give crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Purification was used in the next step.

LCMS (Method B): Rt = 0.77 min, MH ⁺ = 190.1

Intermediate 42: 1-(1-methylethyl)-1 H -indole-2-carbaldehyde

Acetonitrile (50 mL) was added to a flask containing 1H-indole-2-carbaldehyde (500 mg, 3.44 mmol, from Sigma-Aldrich) and cesium carbonate (2245 mg, 6.89 mmol) at rt. Then 1-methylethylmethanesulfonate (1.180 mL, 6.89 mmol) was added dropwise. The reaction was stirred at rt for 1 h and then heated to 95 ° C and stirred for 16 h. The reaction mixture was concentrated in vacuo and the crude product was partitioned between water (100 mL) and Et ₂ O (100mL). The layers were separated and the aqueous layer was further extracted with _{Et 2 O (2 × 50mL)} . The organic phase was dried (Na ₂ SO ₄₎ and concentrated in vacuo to afford a brown oily crude product. The crude product was purified on a pad of EtOAc (EtOAc) elute Appropriate fractions were combined and evaporated in vacuo to crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

LCMS (Method B): Rt = 1.16 min, MH ⁺ = 188.1

Intermediate 43: (2-carbamido-1 H -indol-1-yl)acetonitrile

Potassium tert-butoxide (578 mg, 5.15) was added to N,N-dimethylformamide (DMF) (8 mL) and 1H-indole-2-carbaldehyde (502 mg, 3.46 mmol, available from, for example, Sigma-Aldrich). The reaction mixture was stirred at rt for 1 h under nitrogen. 2-Chloroacetonitrile (0.44 mL, 6.95 mmol) was added dropwise to the reaction mixture and the solution was warmed to 65 &lt;0&gt;C for 1 h. The reaction mixture was cooled to rt and stirred under nitrogen for 1 h. The reaction was reheated to 65 ° C and stirred under nitrogen for 1 h. 2-Chloroacetonitrile (1.1 mL) was added to the reaction mixture and stirred under nitrogen at 65 ° C for 30 min. The reaction mixture was cooled to rt and stirred under nitrogen overnight. The reaction was quenched with water (50 mL)EtOAc. The aqueous layer was further extracted with diethyl ether (2×50 mL). The organic layers were combined and washed with water (2×50 mL). The organic layer was collected, dried using Na ₂ SO _4, passed through a hydrophobic frit and concentrated in vacuo to yield a black solid. The crude product was taken up in a minimum volume of DCM and purified eluting with EtOAc (EtOAc) The appropriate portion and concentrated in vacuo to give a brown oil - (2-acyl -1 H - indol-1-yl) acetonitrile (92mg, 14%). The product was used in the next reaction without further purification.

LCMS (Method B): Rt = 0.87 min, product was not ionized at m/z

Intermediate 44: Ethyl 1-ethyl-6-(methyloxy)-1 H -indole-2-carboxylate

Add 6-methoxy-1H-indole in N,N-dimethylformamide (DMF) (5 mL) to a stirred round bottom flask containing potassium carbonate (1.495 g, 10.82 mmol) under nitrogen. 2-carboxylic acid (502 mg, 2.63 mmol, available from, for example, Amfinecom Inc.). To the reaction mixture was added ethyl bromide (1 mL, 13.40 mmol). The mixture was then heated to 100 ° C and stirred under nitrogen for 2 h. Further, ethyl bromide (0.5 mL), potassium carbonate (828 mg) and N,N-dimethylformamide (DMF) (5 mL) were added and the mixture was stirred at 100 ° C for 3 h. The reaction mixture was concentrated under vacuum to give a white solid (~ 5.2 g). The solid was dried under vacuum. The sample produced >100% yield and was assumed to contain 12.5% of the desired product with inorganic impurities. Purification was not carried out and the crude product was used in the next reaction.

LCMS (Method A): Rt = 1.30 min, MH ⁺ = 248.1

Other examples indicated in the table below were prepared in a manner similar to Intermediate 44:

Intermediate 46: 6-Ethoxy-1-ethyl-1H-indole-2-carboxylic acid ethyl ester

A solution of 6-ethoxy-1H-indole-2-carboxylic acid (434 mg, 2.115 mmol, available from, for example, ACBBlocks) in DMF (5 mL) was added to potassium carbonate (1.461 g, 10.570 mmol). Ethyl bromide (0.789 mL, 10.570 mmol) was added and the reaction mixture was stirred at <RTI ID=0.0># </RTI> <RTI ID=0.0> The solvent was evaporated under reduced pressure to give crystals crystals crystals crystals crystals This was crude for the next reaction without purification.

LCMS (Method A): Rt = 1.38 min, MH ⁺ = 262.11.

Intermediate 47: Ethyl 1-ethyl-5,6-dimethoxy-1H-indole-2-carboxylate

Ethyl 5,6-dimethoxy-1H-indole-2-carboxylate (300 mg, 1.204 mmol, available from, for example, Alfa Aesar) was dissolved in anhydrous N,N-dimethylformamide (DMF) ( The resulting solution was cooled in an ice water bath in 2 mL). Sodium hydride (60% dispersion in mineral oil) (58.6 mg, 1.465 mmol) was added slowly. The resulting solution was stirred in an ice-bath for 1 h then EtOAc (EtOAc:EtOAc. The reaction was allowed to warm to rt overnight. By the addition of saturated NH ₄ Cl (aq) the reaction mixture was quenched. The reaction mixture was diluted with water and EtOAc. The organic phase was separated and washed sequentially with 2M NaOH (aq.) then water. The organic phase was passed through a hydrophobic glass and the solvent was removed in vacuo to afford crude product as an orange solid. The product was purified on a SNAP (20 g) EtOAc column using EtOAc (EtOAc) (EtOAc) The appropriate fractions were combined and the solvent was removed in vacuo to give a white solid. The solid was dried in a vacuum oven to give title compound (m.

LCMS (Method B): Rt = 1.14min, MH + = 278.0.

Intermediate 48: 1-Ethyl-7-fluoro-1 H -indole-2-carboxylic acid

Potassium carbonate (771 mg, 11.2 mmol) was added to a solution of 7-fluoroindolecarboxylic acid (500 mg, 2.79 mmol, e.g. from Matrix Scientific) in DMF (5 mL), followed by ethyl bromide (521 μL, 6.98 mmol) . The reaction mixture was heated at 60 &lt;0&gt;C for 2 h then additional ethyl bromide (521 uL, 6. The reaction mixture was heated at 60 &lt;0&gt;C for additional 2 h then concentrated under reduced pressure to give a crude material.

This material was suspended in a solution of THF (20 mL), water (20 mL) and MeOH (5 mL). The reaction mixture was stirred at rt for 16 h then concentrated EtOAc. The resulting crude product was taken from EtOAc EtOAc m.

LCMS (formic acid) MH+ = 208.0, Rt 1.03 min

Intermediate 49: 7-Bromo-1-ethyl-1 H -indole-2-carboxylic acid

To a solution of 7-bromo-1 H -indole-2-carboxylic acid ethyl ester (1.11 g, 3.73 mmol, for example from Chem-Impex International Inc.) in DMF (15 mL) was added potassium carbonate (2.06 g, 14.92 mmol) followed by the addition of ethyl bromide (1.4 mL, 18.76 mmol). The reaction mixture was heated at 60 &lt;0&gt;C for 1.5 h then concentrated under reduced pressure. LiOH (0.844 g, 35.2 mmol) was added to the crude product, followed by THF (20 mL), water (20mL) and MeOH (5mL). The resulting mixture was stirred at rt under nitrogen for 16 hr then concentrated. 2N HCl (aq.) was added to EtOAc (EtOAc m.

LCMS (formic acid) MH+ = 267.3 / 270.1, Rt = 1.13 min

Intermediate 50: 1-Ethyl-6-(methyloxy)-1 H -indole-2-carboxylic acid

To 1-ethyl-6-methoxy-1H-indole-2-carboxylic acid ethyl ester (estimated 657 mg of the desired starting material, about 5.2 g of crude material with an inorganic material from the previous step) in tetrahydrofuran (THF) Lithium hydroxide monohydrate (316 mg, 13.20 mmol) was added to a heterogeneous mixture of (20 mL), water (20 mL) and methanol (5 mL) and the mixture was stirred at rt overnight (~ 18h). Further, lithium hydroxide monohydrate (314.2 mg) was added to the reaction mixture and stirred for 3 h. Distilled water (5 mL) and lithium hydroxide monohydrate (302.3 mg) were added to the reaction mixture and stirred at rt overnight. The reaction mixture was concentrated under vacuum and 2M EtOAc (20 mL). The resulting solid was collected via filtration and washed with water. Beige solid was collected and dried under high vacuum for 3h, to give 1-ethyl-6- (methyloxy) -1 H - indole-2-carboxylic acid (429mg, 97%).

LCMS (Method B): Rt = 0.93 min, MH ⁺ = 220.1

Other examples indicated in the table below were prepared in a manner similar to Intermediate 50:

Intermediate 52: 6-Ethoxy-1-ethyl-1H-indole-2-carboxylic acid

To 6-ethoxy-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (4.1 g of the crude material from the previous step, 553 mg, 2.15 mmol of the desired starting material) in THF (10 mL) Lithium hydroxide monohydrate (331 mg, 7.89 mmol) was added to a suspension of water (10 mL) and MeOH (2.5 mL). After stirring for 7 h, additional lithium hydroxide monohydrate (331 mg, 7.89 mmol) in water (5 mL). The reaction mixture was stirred at rt overnight and then additional lithium hydroxide monohydrate ( 533 mg, 12. After stirring at rt for 5 h, the reaction mixture was stirred at 40 ° C overnight. The reaction mixture was concentrated under reduced pressure to give a beige solid. Stirring HCl (14 mL of a 2 M solution) was added to the residue with stirring. The resulting solid was collected by suction <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0> M, 87% yield).

LCMS (Method A): Rt = 0.67 min, MH ⁺ = 234.15

Intermediate 53: 5-Cyano-1-ethyl -1H- indole-2-carboxylic acid

To a flask of potassium hydroxide (471 mg, 8.40 mmol) was added dimethyl sulfonium (DMSO) (20 mL) and the mixture was stirred at rt for 10 min. To the reaction mixture was added ethyl 5-cyano-1H-indole-2-carboxylate (500 mg, 2.234 mmol, obtained from, for example, ACB Blocks Ltd.) and stirred under nitrogen at rt for 2.5 h. Ethyl bromide (0.296 mL, 3.97 mmol) was added dropwise and the~~~~~ The reaction was quenched by careful addition of water (50 mL). Et ₂ O (50 mL) was added and the layers were separated. The aqueous layer was further extracted with Et ₂ O ₍₂ × 50mL) and washed with brine (1 × 50mL) The combined organics were washed. The organic layer was then dried (Na ₂ SO ₄₎ and concentrated in vacuo to give a white waxy -1H- 5-cyano-1-ethyl-indole-2-carboxylic acid ethyl ester (338mg, 1.395mmol, 59.8 %Yield). The aqueous solution was acidified to pH = 4 using 5.0M HCl. A white precipitate was filtered and evaporated in vacuo to give white powder, 5--cyano-1-ethyl-1H-indole-2-carboxylic acid (328 mg, 1.531 M, 65.6% yield).

LCMS (Method B): Rt 0.86 min.

Intermediate 54: 1-Ethyl-5,6-dimethoxy-1H-indole-2-carboxylic acid

Ethyl 1-ethyl-5,6-dimethoxy-1H-indole-2-carboxylate (305 mg, 1.100 Methyl) was dissolved in a mixture of water (2 mL), methanol (1 mL) and tetrahydrofuran (THF) (4 mL). To this solution was added lithium hydroxide monohydrate (138 mg, 3.30 mmol). The solution was stirred overnight. The solvent was removed in vacuo and the obtained solid was redissolved in THF (4mL) and water (2mL). The reaction was overnight. The solution was then heated to 40 ° C for 1 h. The solvent was removed under vacuum and the resulting solid was dried in a vacuum oven for one week. This gave the title compound (302 mg).

LCMS (Method B): Rt 0.80 min, MH+ = 249.9.

Intermediate 55: N , N '-3,4-pyridinediylbis(2,2,2-trifluoroacetamide), trifluoroacetate

To a solution of pyridine-3,4-diamine (1 g, 9.16 mmol, e.g. from Sigma-Aldrich) in dichloromethane (DCM) (28 mL), TFAA (3.24 mL, 22.91 mmol) . The reaction was stirred at rt for 30 min. A solid "ball" is formed after about 15 minutes. LCMS analysis of the liquid mainly showed the product, but the analysis of the solid mainly showed the starting material. The reaction mixture was sonicated for 1 h. During the ultrasonic treatment process, the reaction mixture was heated slightly (about 35 ° C) and the solids were small, but a two phase mixture was produced. The analysis of the higher phase mainly showed the product and the lower phase showed the product, no starting material, but some monoprotected pyridine. The reaction mixture was concentrated in vacuo and dried in vacuo overnight to afford a colourless oil, s. The crude product was taken up in dichloromethane (DCM) (10 mL) and TFAA (0.647 <RTIgt; The reaction was sonicated for 30 min and concentrated in vacuo to give -N,N'-(pyridine-3,4-diyl)bis(2,2,2-trifluoroacetamide), trifluoroacetate (4.28 g, 8.76 mmol, 96% yield). This material was used in the subsequent reaction without further purification.

LCMS (Method B): Rt = 0.82 min, MH ⁺ = 301.9

Intermediate 56: 2,2,2-trifluoro-N-(4-methylpyridin-3-yl)acetamide, trifluoroacetate.

Carefully add 2,2,2-trifluoroacetic anhydride to a solution of 4-methylpyridin-3-amine (1 g, 9.25 mmol, available from, for example, Atlantic SciTech Group, Inc.) in anhydrous dichloromethane (10 mL). (1.27 mL, 10.2 mmol). The resulting solution was stirred at rt for 5 min. The reaction mixture was concentrated in vacuo to give title crystals (30g,

LCMS (Method B): Rt 0.44min, m / z204.9 (MH +).

Intermediate 57: 5-(2,2,2-trifluoroethylamino)nicotinic acid methyl ester, trifluoroacetate

Prepared from 5-aminonicotinic acid methyl ester (purchased, for example, from Sigma-Aldrich) in a similar manner to intermediate 56.

LCMS (Method B): Rt = 0.75 min, MH ⁺ = 248.9

Intermediate 58: 2,2,2-Trifluoro-N-(5-methylpyridin-3-yl)acetamide

Add sodium hydride (304 mg, 7.60 mmol) to 5-methylpyridin-3-amine (274 mg, 2.53 mmol, available from, for example, Sigma-Aldrich) in N,N-dimethylformamide (DMF) (4 mL). And TFAA (0.716 mL, 5.07 mmol) and the mixture was stirred at room temperature under nitrogen overnight. Water was added and the product was extracted into DCM (×3). The combined organic layers were evaporated to give a brown oil which was dried under high vacuum to afford title compound (512 mg, 79%).

LCMS (Method B): Rt = 0.50 min, MH+ = 205.0.

Intermediate 59: 2,2,2-Trifluoro-N-(5-fluoropyridin-3-yl)acetamide

To a solution of 5-fluoropyridin-3-amine (548 mg, 4.89 mmol, available from, for example, Fluorochem) in dichloromethane (10 mL) was added TFAA (0.898 mL, 6.35 mmol). Stir for 30 min. The solvent was removed and the residue was dried EtOAcjjjjjjjjj

LCMS (Method B): Rt = 0.74 min, MH+ = 209.0.

Intermediate 60: N,N'-(pyridine-3,5-diyl)bis(2,2,2-trifluoroacetamide)

Add TFAA (1.773 mL, 12.56 mmol) to pyridine-3,5-diamine (527 mg, 4.83 mmol, available from, for example, 3B Scientific Corporation) in dichloromethane (10 mL). Stir under nitrogen overnight. The solvent was removed and the residue was washed with EtOAc EtOAc (EtOAc)

LCMS (Method B): Rt = 0.80 min, MH+ = 302.0.

Intermediate 61: 2,2,2-trifluoro-N-(5-methoxypyridin-3-yl)acetamide, trifluoroacetate

5-methoxypyridin-3-amine (975 mg, 7.85) in dichloromethane (5 mL) Methanol (1.442 mL, 10.21 mmol) was added to mmol, purchased from, for example, J&W Pharmlab, and the reaction was stirred for one week. The solvent was removed and the residue was crystallisjjjjjjjjjj

LCMS (Method B): Rt = 0.65 min, MH+ = 220.9.

Intermediate 62: 3-(2,2,2-Trifluoroethylamino)isonicotinic acid methyl ester

To a solution of 3-aminoisonicotinin methyl ester (362 mg, 2.379 mmol, available from, for example, Atlantic Research Chemicals) in dichloromethane (D) (8 mL) was added TFAA (0.437 mL, 3.09 mmol) and Stir under nitrogen at rt for 30 min. The solvent was removed and the residue was dried <RTI ID=0.0>

LCMS (Method B): Rt = 0.84 min, MH+ = 248.9.

Intermediate 63: N , N '-3,4-Hexidopyridinediylbis(2,2,2-trifluoroacetamide), acetate

N,N'-(pyridine-3,4-diyl)bis(2,2,2-trifluoroacetamide), trifluoroacetate (780 mg, 1.879 mmol) was dissolved in acetic acid (10 mL) and Hydrogenation was carried out in a H-cube overnight at 100 ° C and 100 bar through a 10% Pd/C catalyst column (100 mg, 0.940 mmol) (the inlet tube was placed in a receiver vessel to allow the reaction mixture to circulate continuously). LCMS showed no starting pyridine. The reaction mixture was concentrated in vacuo and aq. toluness (2.times.15mL) to afford the desired product -N,N'-(hexahydropyridine-3,4-diyl) bis (2,2,2) -Trifluoroacetamide), acetate (686 mg, 1.868 mmol, 99% yield). This material was used in the subsequent reaction without further purification or characterization.

LCMS (Method B): Rt = 0.46 min, MH ⁺ = 308.0

Intermediate 64: 2,2,2-Trifluoro-N-(4-methylhexahydropyridin-3-yl)acetamide

2,2,2-trifluoro-N-(4-methylpyridin-3-yl)acetamide, trifluoroacetate (1.5 g) using a 10% Pd/C catalyst column at 80 bar and 100 °C A solution of 4.71 mmol) in acetic acid (15 mL) was passed through an H-cube device (flow rate 1 mL/min). The solution was circulated through the machine for 6 h and concentrated under vacuum. The residue was taken up in methanol and passed through an amine propyl column (20 g) eluting with methanol. The collected fractions were concentrated in vacuo to give the desired product ( 549 g, 55%). The product is a 2:1 mixture of cis- isomer and trans- isomer.

¹ H NMR (CDCl ₃ ) δ: 7.42 (br.s., 1H), 6.88 (br.s., 1H), 4.07 (br.s., 1H), 3.62-3.49 (m, 1H), 3.16 ( Dd, J = 12.0, 3.9 Hz, 1H), 3.06-2.95 (m, 1H), 2.95-2.89 (m, 1H), 2.79 (dd, J = 11.6, 2.0 Hz, 1H), 2.65-2.51 (m, 1H), 2.42 (dd, J = 12.1, 9.6 Hz, 1H), 1.82-1.71 (m, 1H), 1.64-1.51 (m, 1H), 1.51-1.42 (m, 1H), 1.36-1.18 (m, 1H), 0.98 (d, J = 6.6 Hz, 1H), 0.87 (d, J = 6.8 Hz, 2H).

Intermediate 65: 5-(2,2,2-Trifluoroethylamino)hexahydropyridine-3-carboxylic acid methyl ester

Prepared from 5-(2,2,2-trifluoroethylamino) nicotinic acid methyl ester, trifluoroacetate salt in a similar manner to intermediate 64. The product is a 1:1 mixture of cis and trans isomers.

¹ H NMR (CDCl ₃ ) δ: 7.75 (br.s., 1H), 7.08 (br.s., 1H), 4.23-4.15 (m, 1H), 4.04-3.92 (m, 1H), 3.74 (s) , 3H), 3.70 (s, 3H), 3.29-2.45 (m, 10H), 2.27-1.74 (m, 4H).

Intermediate 66: 2,2,2-trifluoro-N-(5-methylhexahydropyridin-3-yl)acetamide, acetate, a mixture of non-image isomers

2,2,2-Trifluoro-N-(5-methylpyridin-3-yl)acetamide (512 mg, 2.508 mmol) was dissolved in acetic acid (10 mL) and passed through 10 at 100 ° C and 100 bar. A % Pd/C catalyst column (100 mg, 0.940 mmol) was hydrogenated overnight in H-cube. The solvent was removed and the residue was azeotroped with toluene. The residue was dried under high vacuum for 1 h to give a brown oil, which was taken in the next step ( 745 mg, 110%).

LCMS (Method B): rt = 0.35 min.

Intermediate 67: 5-methylhexahydropyridin-3-ol, a mixture of non-image isomers

5-Pyridin-3-ol (507 mg) in acetic acid (30 mL) (about 0.15 M solution) using a Pd/C catalyst column (49.4 mg, 0.465 mmol) as a catalyst and a pressure of 100 ° C and 100 bar. 4.65 mmol, purchased from, for example, Alfa Aesar) was hydrogenated by means of H-cube and was constantly circulated overnight at 1 mL/min. The solvent was removed and the residue was loaded onto a 10 g SCX-2 column, washed with methanol and then eluted with 2M methanol ammonia. The solvent was removed and the~~~~~~~

LCMS (Method B): Rt = 0.38 min.

Intermediate 68: 2,2,2-trifluoro-N-(5-fluorohexahydropyridin-3-yl)acetamide, acetate, a mixture of non-image isomers

2,2,2-Trifluoro-N-(5-fluoropyridin-3-yl)acetamide (800 mg, 3.84 mmol) was dissolved in acetic acid (10 mL) and passed 10% at 100 ° C and 100 bar. A Pd/C catalyst column (100 mg, 0.940 mmol) was hydrogenated in H-cube for 3 h. The solvent was removed and the residue was dried under high vacuum overnight. The residue was redissolved in acetic acid and hydrogenated in H-cube for 6 h at 100 ° C and 100 bar through a 10% Pd/C catalyst column (100 mg, 0.940 mmol). The solvent was removed and the residue was dried EtOAc mjjjjjjj

LCMS (Method B): Rt = 0.229 min.

Intermediate 69: N,N'-(hexahydropyridine-3,5-diyl)bis(2,2,2-trifluoroacetamide), acetate, a mixture of non-image isomers

N,N'-(pyridine-3,5-diyl)bis(2,2,2-trifluoroacetamide) (2.2 g, 7.31 mmol) in acetic acid (15 mL) was passed through H-cube Pd/C 10% catalyst column (30 mg, 0.282 mmol) was hydrogenated and cycled overnight. The solvent was removed and the residue was dried <RTI ID=0.0>

LCMS (Method B): Rt = 0.46 min, MH+ = 308.0.

Intermediate 70: 3-(2,2,2-Trifluoroethylamino)hexahydropyridine-4-carboxylic acid methyl ester, acetate, a mixture of non-image isomers

Preparation of 3-(2,2,2-trifluoroethylamino)isonicotinic acid methyl ester from trifluoroacetic acid salt in a similar manner to Intermediate 69

LCMS (Method B): Rt = 0.34 min, MH+ = 255.0.

Intermediate 71: 2,2,2-trifluoro-N-(5-methoxyhexahydropyridin-3-yl)acetamide, acetate, mixture of non-image isomers

2,2,2-Trifluoro-N-(5-methoxypyridin-3-yl)acetamide, trifluoroacetate (2000 mg, 5.98 mmol) in acetic acid (10 mL) at 100 ° C at 100 The bar was hydrogenated in H-cube for 78 h. The solvent was removed and the residue was dried under high vacuum to afford brown oil (1, 985 g, 116%).

LCMS (Method B): Rt = 0.37 min.

Intermediate 72: 2,2,2-Trifluoro-N-((cis)-5-methylpyrrolidin-3-yl)acetamide, trifluoroacetate

(cis)-4-amino-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (120 mg, 0.599 mmol) in methylene chloride (DCM) (2 mL) In the following literature: Et ₃ N (0.167 mL, 1.198 mmol) and TFAA (0.085 mL, 0.599 mmol) were added to ACS Med. Chem. Lett. 2011 , 2, 142, and the reaction was stirred for one week. The reaction mixture was partitioned between DCM and water (x3). The combined organic layers were washed with water (x 2) and solvent was evaporated to give a clear oil, which was dried under high vacuum overnight to afford (cis)-2-methyl-4-(2,2,2 -Trifluoroacetamido)pyrrolidine-1-carboxylic acid tert-butyl ester (118 mg).

(cis)-(1-(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-) in methylene chloride (DCM) (1 mL) 1H-benzo[d]imidazol-5-carbonyl)pyrrolidin-3-yl)carbamic acid TCA (0.5 mL, 6.49 mmol) was added <RTI ID=0.0> The solvent was removed and the residue was dried EtOAc EtOAcjjjjjjjj

LCMS (Method B): rt = 0.30 min.

Intermediate 73: 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester

5,6-Dihydropyridine-1(2H)-carboxylic acid benzyl ester (15.1 g, 69.5 mmol) (purchased from, for example, Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) with ice-cooling. 3-Chlorobenzyl peroxyacid (16.79 g, 97 mmol) was added portionwise to the stirred solution. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. To a stirred solution of the _5% NaS ₂ O 5 solution (200mL) was added dropwise to the organic layer. At the end of the addition, the mixture was stirred for additional 1 h, then the layers were separated and the aqueous layer was re-extracted with DCM (50mL×2). The organics were combined and washed with aq. 5% K ₂ CO ₃ (100 mL×3) then brine (100 mL). At this stage, the peroxide test showed the presence of 25 mg/mL peroxide in the organic layer. Therefore, organics were added to a stirred 5% NaS ₂ O ₅ solution (aq.) (200 mL) and the obtained mixture was stirred for 1 h. The peroxide test now shows <0.5 mg/mL peroxide. The layers were separated and the aqueous layer was washed further with DCM (2×50 mL). Then the combined organics were dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product was a pale golden oil. The crude product was purified by EtOAc (EtOAc:EtOAc) The appropriate fractions were combined with EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj %Yield).

LCMS (Method B): Rt = 0.88 min, MH ⁺ = 234.2

Intermediate 74: trans- 3-(( t- butoxycarbonyl)amino)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester

Three separate reaction schemes were carried out under the same reaction conditions as outlined below. If the amount of reagent/solvent varies, the specific amounts used are summarized in the table. The crude materials from the three reactions were combined for purification as indicated:

7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl ester (A) in 25-30% aqueous ammonium hydroxide (150 ml, 3766 mmol) and ethanol (70 ° C) The solution in 100 mL) was stirred in a HASTC alloy bomb for 5 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo to half (note that emit large amounts of NH _3). The resulting solution was diluted with brine (50 mL) and EtOAc evaporated. The aqueous layer was then further extracted with 10% MeOH / DCM (3 x 50 mL). The combined organic layers were dried (Na ₂ SO ₄₎ and concentrated in vacuo to yield an amine intermediate as a yellow oil. The oily residue was diluted with dropwise addition of dichloromethane (DCM) (B) and triethylamine (C) and Boc ₂ O (D). The reaction was allowed to stir for 2 h. LCMS showed complete reaction into two regioisomeric products with similar Rt. The reaction mixture (100 mL) quenched with saturated NH ₄ Cl (aq) and the layers separated. The aqueous layer was further extracted with DCM (2×75 mL). The combined organics were dried through a hydrophobic glass and the solvent removed under vacuum to yield a white gum.

The crude materials from the three reactions were combined for purification: the combined residue was dissolved in DCM and taken up in two portions and used on a 340 g of cerium dioxide column by column chromatography. Purification by gradient of 100% ethyl acetate / cyclohexane. The appropriate fractions are combined and evaporated in vacuo to produce two major products:

The first elution peak from the column: trans- 4-(( t- butoxycarbonyl)amino)-3-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester as a white solid (10.492 g, 29.9 mmol) , 59% yield) (regional isomers are not desired).

The second elution peak from the column: white solid trans-3 - ((tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (6.485g, 18.51mmol , 37% yield) (desired regioisomers indicated above).

LCMS (Method B): Rt = 0.96 min, MH ⁺ = 351.2

Intermediate 75: cis- 4-(benzylideneoxy)-3-(( t- butoxycarbonyl)amino)hexahydropyridine-1-carboxylic acid benzyl ester

To a solution of triphenylphosphine (5.83 g, 22.24 mmol) in tetrahydrofuran (THF) (60 mL), EtOAc (EtOAc) To the suspension was added trans- 3-(( t- butoxycarbonyl)amino)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester (6.495 g, 18.54 mmol) in tetrahydrofuran (THF) (75 mL) The suspension was then added with benzoic acid (2.72 g, 22.24 mmol). The reaction mixture was cleared to a yellow solution and stirred for 2 h. LCMS analysis showed product formation, however, the SM peak was obscured by by-products, so it was difficult to confirm completion of the reaction. The reaction was stirred overnight (20 h). The reaction mixture was concentrated under vacuum. The residue was purified by chromatography on EtOAc. The residue was taken up in EtOAc EtOAc EtOAc EtOAc. Appropriate fractions were combined and the solvent was evaporated in vacuo to give a pale yellow oily crude product was cis -3-4- (benzoyl-yloxy) - ((tert-butoxy carbonyl) amino) piperidine - Benzoic acid benzyl ester (8.11 g, 17.84 mmol, 96% yield).

LCMS (Method B): Rt = 1.27min, MH + = 455.3.

Intermediate 76: cis- 3-(( t- butoxycarbonyl)amino)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester

Intermediate 77: (3 S, 4 R ) -3 - (( tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester

Intermediate 78: (3 R, 4 S ) -3 - (( tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester

Benzyl cis- 4-(benzylideneoxy)-3-(( t- butoxycarbonyl)amino)hexahydropyridine-1-carboxylate (8.11 g, 17.84 mmol) in ethanol (160 mL) A solution of potassium carbonate (3.70 g, 26.8 mmol) in water (80 mL) was added and the mixture was stirred at 70 ° C for 20 h. The reaction mixture was concentrated to 1/3 EtOAc (EtOAc)EtOAc. The combined organics were collected and dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product as a colorless oil. The crude product was then purified by column chromatography on a pad of EtOAc ( EtOAc) EtOAc. Appropriate fractions were combined and evaporated in vacuo to yield the desired product as a white foam cis -3 - ((tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (5.54 g, 15.81 mmol, 89% yield).

LCMS (Method B): Rt = 0.98 min, MH ⁺ = 351.2

1 g of the racemic product was submitted for chiral purification chromatography using chiral HPLC method B. Successful resolution of isomers:

Isomer was obtained as a colorless oily 1- (3 S, 4 R) -3 - (( tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (405mg, 1.156mmol , 6.48% yield).

LCMS (Method B): Rt = 0.97 min, MH ⁺ = 351.2

Chiral HPLC (Method A): 100% ee.

Isomer was obtained as a colorless oily 2- (3 R, 4 S) -3 - (( tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (411mg, 1.173mmol , 6.57% yield).

LCMS (Method B): Rt = 0.99 min, MH ⁺ = 351.2

Chiral HPLC (Method A): 95% ee.

The remaining 4.5 g of the racemate was also presented for chiral purification using chiral HPLC method C. Successful resolution of isomers:

Isomer was obtained as a colorless oily 1- (3 S, 4 R) -3 - (( tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (1.94g, 5.54 M, 31.0% yield).

LCMS (Method B): Rt = 0.98 min, MH ⁺ = 351.2

Chiral HPLC (Method A): 98.7% ee.

Isomer was obtained as a colorless oily 2- (3 R, 4 S) -3 - (( tert-butoxy carbonyl) amino) -4-hydroxy-piperidine-1-carboxylic acid benzyl ester (1.92g, 5.48 M, 30.7% yield).

LCMS (Method B): Rt = 0.97 min, MH ⁺ = 351.1

Chiral HPLC (Method A): 96, 3% ee.

Intermediate 79: tert-butyl ((3 S ,4 R )-4-hydroxyhexahydropyridin-3-yl)carbamate

Was added (3 S, 4 R) -3 to the hydrogenation flask containing 10% Pd / C (0.059g, 0.554mmol) in the - ((tert-butoxy carbonyl) amino) -4-hydroxy-hexahydro-l - acid benzyl ester (1.94g, 5.54mmol) in ethanol (48mL) in the solution, the flask was evacuated and backfilled N ₂ (× 3). The flask was again evacuated and then backfilled H ₂ (× 3). Then introducing sufficient H ₂ into the burette to allow the reaction was complete and the system shut down and the flask was stirred under an atmosphere of H ₂ overnight. The reaction mixture was filtered through EtOAc (EtOAc)EtOAcEtOAcEtOAc The combined filtrates were concentrated in vacuo to give an oily product as a solid cream - ((3 S, 4 R ) -4- hydroxy-hexahydro-3-yl) carbamic acid tert-butyl ester (1.13 g of, 5.22 mmol, 94% yield).

LCMS (Method B): Rt = 0.40 min, MH ⁺ = 217.1

Intermediate 80: tert-butyl ((3 R , 4 S )-4-hydroxyhexahydropyridin-3-yl)carbamate

Hydrogenation of 3-(( t- butoxycarbonyl)amino)-4-hydroxyl group using H-cube (setting: 25 ° C, full H ₂ mode, 1 mL/min flow rate) and 10% Pd/C CatCart 30 as a catalyst A solution of benzyl hexahydropyridine-1-carboxylate (141 mg, 0.402 mmol) in methanol (8.05 mL). The eluent was evaporated in vacuo to give (4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester (85.1 mg, 0.393 mmol, 98% yield).

¹ H NMR (DMSO-d ₆ , 393 K): 5.60 (1H, br s, NH), 3.77 (1H, dt, CH), 3.45 (1H, ddd, CH), 2.80 (1H, ddd, C H _A H _B ), 2.72 (1H, dd, C H _A H _B ), 2.63 (1H, dd, CH _A H _B ), 2.55-2.48 (1H, obs, CH _A H _B ), 1.59-1.53 (2H, m, CH ₂ ), 1.42 (9H, s, 3 × CH ₃ ).

Evidence for Absolute Stereochemistry of Intermediates 79 and 80

The absolute configuration of the intermediates 79 and 80 was assigned using a VCD analysis from the beginning. The trust level for this allocation is estimated to be >99%.

theoretical analysis:

‧Conformational search: MOE random search using MMFF94x force field

‧ model chemistry: opt freq number = (noraman, vcd) b3lyp / dgdzvp

‧Conformational analysis: Fractional populations estimated using Boltzmann statistics

‧Lorentzian bandwidth: 6cm ^-1

‧ Frequency scale factor: 0.975

‧ Estimation of the limits of trust: CompareVOA (BioTools, Inc.) analysis

experiment:

‧ spectrometer: at 4cm ^-1 BioTools in operation of Chiral IR - 2X FT-VCD spectrometer

‧ Frequency range: 2000-800cm ^-1

‧PEM correction: PEM corrected at 1400cm ^-1

‧PEM delay setting: PEM1=0.250*λ; PEM2=0.260*λ

‧ Scanning method: single 4h scan; total = 3120 × 4 = 12480 scan) scan; t about 6h.)

‧ Solvent: CDCl ₃

‧Concentration: about 10mg/250uL

‧ Baseline calibration method: Modified half difference (VCDE1 (corrected) = VCDE1 minus VCDE2; VCDE2 (corrected) = VCDE2 minus VCDE1)

‧Additional processing: Savitsky-Golay 9-point smoothing

Estimated reliability level

The limits of trust in this study were estimated using CompareVOATM (BioTools, Inc.), an automated tool for quantifying the degree of agreement between two sets of spectral data.

The degree of reliability (trust limit) was evaluated using the absolute values of the two parameters: the total proximity similarity of the VCD correction (TNS (VCD)) and the image isomer similarity index (ESI).

The degree of reliability based on CompareVOA analysis is as follows:

CompareVOA results: Spectral range: 1760-950cm ^-1

Ignore area: none

Scope of statistical analysis (minimum 400cm ^-1 ): 810cm ^-1

Width of the triangle weighting function: 20cm ^-1

TNS (VCD): 85.1 (absolute value)

ESI: 82.8 (absolute value)

Optimized scale factor: 0.975

Estimated trust level: >99%

Intermediate 81: (+/-)-( cis- 4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

Prepared from cis- 3-(( t- butoxycarbonyl)amino)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester in a similar manner to the intermediate 80.

¹ H NMR (CDCl ₃ ): 5.31 (1H, br s, NH), 4.00-3.75 (2H, m, 2 x CH), 3.04-2.89 (2H, m, 2 x C H _A H _B ), 2.81 ( 1H, dd, CH _A H _B ), 2.64 (1H, ddd, CH _A H _B ), 1.83-1.60 (2H, m, CH ₂ ), 1.50 (9H, s, 3×CH ₃ ).

Intermediate 82: (+/-)-( trans- 4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

-4-hydroxy-piperidine-1-carboxylic acid benzyl ester was prepared ((tert-butoxy carbonyl) amino) - Intermediate 80 in a similar manner from the trans-3.

¹ H NMR (CDCl ₃ ): 4.74 (1H, br, NH), 3.48 (1H, ddd, CH), 3.42-3.31 (1H, m, CH), 3.24 (1H, dd, C H _A H _B ) , 3.04 (1H, dt, C H A H B), 2.58 (1H, ddd, CH A H B), 2.38 (1H, dd, CH A H B), 2.02 (1H, dq, C H A H B) , 1.53-1.40 (10H, m, CH _A H _B , 3 × CH ₃ ).

Intermediate 83: (+/-)- (cis) -3-(( t- butoxycarbonyl)amino)-4-ethoxyhexahydropyridine-1-carboxylic acid benzyl ester

A suspension of sodium hydride (32.3 mg, 1.346 mmol) in THF (9 mL) was stirred at EtOAc. Add a solution of 3-(( t- butoxycarbonyl)amino)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester (393 mg, 1.122 mmol) in THF (5 mL). Stir under 45 min. The reaction mixture was placed in an ice-NaCl bath at -25 ° C, then ethyl trifluoromethanesulfonate (0.159mL, 1.234mmol). After 10 min, the ice-NaCl bath was replaced with an ice water bath and the reaction mixture was stirred for 1.5 h. The reaction mixture was then stirred at rt for 4.5 h and kept in a freezer overnight. The reaction mixture was neutralized with glacial acetic acid (15 drops) and solvent was evaporated under reduced pressure to give a clear oil. The residue was dissolved in EtOAc (50mL), and extracted with NaHCO _{3 (3} × 70mL) and washed with brine (70mL). The organic extracts were combined and dried via a hydrophobic glass. The solvent was evaporated under reduced pressure to give a clear oil. The residue was loaded onto a 50 g SNAP EtOAc column and purified by EtOAc (EtOAc) Appropriate fractions were combined and concentrated under reduced pressure to yield a clear oily crude product 3 - ((tert-butoxy carbonyl) amino) -4-ethoxy-piperidine-1-carboxylic acid benzyl ester (60mg, 0.159 mmol, 14.14% yield). This product was used in the subsequent reaction without further purification.

Intermediate 84: (+/-)-( trans )-3-(( t- butoxycarbonyl)amino)-4-methoxyhexahydropyridine-1-carboxylic acid benzyl ester

To ( trans )-3-(( t- butoxycarbonyl)amino)-4-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester (553 mg, 1.478 mmol) in tetrahydrofuran (THF) (20 mL) Sodium hydride (60% in mineral oil) (76 mg, 1.894 mmol) was added portionwise over ice cold. After the addition, the resulting mixture was stirred at 0 ° C for 1 h. Methyl iodide (0.118 mL, 1.894 mmol) was then added dropwise at 0 °C. After the addition, the mixture was allowed to warm to rt and stirred for 20 h then the mixture was concentrated in vacuo. The residue was taken up in DCM and loaded onto a Biotage SNAP column (100 g). The column was eluted with EtOAc (0-60%, 20 CV). One major product and a slightly more polar secondary product - both were visualized by TLC using vanillin spray. The main product was collected to give the desired product (336.3mg) as a white solid.

LCMS (Method B): Rt = 1.11 min, MH ⁺ = 365.1

Intermediate 85: (+/-)- (cis) -(4-ethoxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

Hydrogenation of 3-(( t- butoxycarbonyl)amino)-4-ethoxyl using H-cube (set: 25 ° C, full H ₂ mode, 1 mL/min flow rate) and 10% Pd/C CatCart 30 column A solution of benzyl hexahydropyridine-1-carboxylate (54 mg, 0.143 mmol) in MeOH (3 mL). The solvent was evaporated under reduced pressure to give crystals crystals crystal crystals crystals This product was used in the next step without purification.

Intermediate 86: (+/-)-(( trans )-4-methoxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

Preparation of ( 3S , 4S )-3-(( t- butoxycarbonyl)amino)-4-methoxyhexahydropyridine-1-carboxylic acid benzyl ester in a similar manner to Intermediate 85

Intermediate 87: (R) -3-azido-1,2,3,6-tetrahydropyridine

To a 5-azido-5,6-dihydropyridine-1( 2H )-carboxylic acid tert-butyl ester at rt under nitrogen (preparation of this intermediate is reported in Synlett , 2006 , 13 , 2109-2113 Trifluoroacetic acid (1 mL, 12.98 mmol) was added to a solution of EtOAc (EtOAc). The mixture was stirred for 40 min and then concentrated in vacuo. The remaining residue was taken up in DCM and washed with NaHCO ₃ (saturated). The organic layer was dried (Na ₂ SO _4), filtered and concentrated to low volume. The material thus obtained was used in the next step without further purification.

LCMS (Method B): Rt = 0.21 min, MH ⁺ = 125.0

Intermediate 88: 4-(Methylamino)-3-nitrobenzoic acid methyl ester

To 4-methyl-3-nitrobenzoic acid methyl ester (5 g, 23.19 mmol) (available from, for example, Lancaster Synthesis Ltd.) in N,N-dimethylformamide (DMF) under nitrogen at rt ( Methylamine (2M in THF) (23.19 mL, 46.4 mmol) was added to a solution. The reaction mixture was heated to 80 ° C and stirred overnight. LCMS showed the major peak product, but the reaction was not yet complete. Additional methylamine (2M in THF, 10 mL) was added and the mixture was warmed to <RTIgt; Methylamine (2M in THF, 6 mL) was added and the mixture was stirred at rt for 1 h and stirred at 70 ° C for 72 h. Additional methylamine (2M in THF, 10 mL) was added and the mixture was warmed to &lt The reaction was cooled to rt and then the product was precipitated by water (50 mL). The resulting suspension was cooled to 0 °C and then filtered. The residue was further washed with water (3 x 25 mL) and dried on a pad for about 15 min. Collect solids and dry in vacuum to The title compound (4.54 g, 21.60 mmol, m.

LCMS (Method B): Rt = 0.69 min, MH ⁺ = 197.2

Intermediate 89: 4-(Methylamino)-3-nitrobenzoic acid

Methyl 4-(methylamino)-3-nitrobenzoate (1.82 g, 8.66 mmol) was dissolved in 1:1 THF (41.4 mL) and water (41.4 mL). To this was added lithium hydroxide (1.817 g, 43.3 mmol). The reaction mixture was cooled to 0 ℃ and by adding 5M HCl (about 20mL, until a pH of about 5) Acidification - bright yellow precipitate was formed, the slurry was filtered and the residue was washed with distilled _{H 2 O (2 × 30mL)} . The residue was taken and dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI><RTIgt;</RTI><RTIgt; This product was used in the subsequent reaction without further purification.

LCMS (formic ^{acid): Rt = 0.69min, MH +} = 197.2.

Intermediate 90: 4-Chloro-2-methyl-5-nitrobenzoic acid

To 4-Chloro-2-methylbenzoic acid (2.4 g, 14.07 mmol, purchased from, for example, Sigma-Aldrich) was added concentrated sulfuric acid (12 mL, 225 mmol) and the reaction mixture was cooled to -20 °C. Fumigation nitric acid (0.754 mL, 16.88 mmol) was added at this temperature, then the reaction mixture was warmed to rt. Stirring was continued for 2 h at rt. The reaction mixture was partitioned between water (50 mL) andEtOAc (EtOAc) The ethyl acetate layer was allowed to stand overnight, after which crystals were formed. The crystals were removed by filtration to give 4-chloro-2-methyl-5-nitrobenzoic acid (389 mg, 1.804 mmol, 12.83% yield).

LCMS (Method C): Rt 0.91 min.

Intermediate 91: 4-Chloro-2-methyl-5-nitrobenzoic acid methyl ester

To a solution of 4-chloro-2-methyl-5-nitrobenzoic acid (430 mg, 1.995 mmol) in EtOAc (EtOAc) Concentrated hydrochloric acid (200 μL) was added and the reaction was heated at 80 ° C for 1 h. The reaction mixture was cooled to rt. Water (100 mL) was added and the aqueous layer was basified to pH 14 using 2M aqueous sodium hydroxide and extracted with ethyl acetate (3×100 mL). The organic layers were kept on one side and used later.

The aqueous layer was acidified with cone. EtOAc and EtOAc (EtOAc) (EtOAc) A 2M aqueous solution of hydrochloric acid (10 mL, 20.00 mmol) was added to EtOAc EtOAc. The reaction mixture was cooled to rt. Water (100 mL) was added and the aqueous layer was basified to pH 14 using 2M aqueous sodium hydroxide and extracted with ethyl acetate (3×100 mL).

The organics were combined (the organics were added previously), dried using a hydrophobic glass and evaporated in vacuo to leave 4-chloro-2-methyl-5-nitrobenzoic acid methyl ester (326 mg, 1.420 mmol, 71.2 %Yield).

LCMS (Method B): Rt 1.11 min.

Intermediate 92: 2-methyl-4-(methylamino)-5-nitrobenzoic acid methyl ester

2M methylamine in THF was added to 4-chloro-2-methyl-5-nitrobenzoic acid methyl ester (321 mg, 1.398 mmol) in N,N-dimethylformamide (2.5 mL). 2.80 mL, 5.59 mmol) and the reaction mixture was stirred at 80 ° C overnight. The reaction mixture was purged under a stream of nitrogen. Add to Methanol (5 mL) and water (5 mL), and the solid formed was removed by filtration and dried in a vacuum oven to give 2-methyl-4-(methylamino)-5-nitrobenzene as a yellow solid. Methyl formate (264 mg, 1.177 mmol, 84% yield).

LCMS (Method B): Rt 1.02 min, MH+ = 225.

Intermediate 93: 3,4-Diamino-5-methylbenzoic acid methyl ester

To a solution of 3,4-diamino-5-methylbenzoic acid (1 g, 6.02 mmol) (purchased from, for example, Parkway Scientific LLC) in methanol (30 mL) was added 2M aqueous hydrochloric acid (30.1 mL, 60.2 mmol). The mixture was heated at 65 ° C for two nights. The reaction mixture was concentrated under reduced pressure and applied to a 2×2 g Isolute Sorbent 103 column. The column was washed with water and eluted with methanol. The methanol fraction was evaporated under reduced pressure. The residue was taken up in dichloromethane / methanol and purified eluting with EtOAc (EtOAc) Appropriate fractions were combined and evaporated <RTI ID=0.0></RTI> tojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

LCMS (Method B): Rt 0.50 min, MH.

Intermediate 94: (R)-(1-(4-bromopyridin-3-nitrobenzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

4-Chloro-3-nitrobenzoic acid (30 g, 149 mmol, purchased from, for example, Apollo Scientific) was mixed with SOCl ₂ (200 mL, 2756 mmol) and stirred at 80 ° C for 2 h. Toluene (500 mL) was added. After evaporation of the solvent, the product containing solution was used directly in the next step. 4-Chloro-3-nitrobenzimidium chloride (29 g, 132 mmol), ( R )-hexahydropyridin-3-ylaminocarbamic acid tert-butyl ester at 0 ° C to 20 ° C under N ₂ ( 25 g, 124 mmol) and DIPEA (66 g, 512 mmol). The reaction was quenched into ice / H ₂ O (about 100g) was added and HCl (to pH 1). The organic phase was washed with NaHCO ₃ (aq, 100 mL, to pH 8), dried (Na ₂ SO ₄₎ and evaporated in vacuo. The crude product was purified by chromatography on silica gel eluting with DCM / MeOH = 80:1. This gave the title compound (30 g).

LCMS (Method B): Rt = 1.06 min, M+H ⁺ = 384.1

Intermediate 95: ((3 R) -1 - {[4- ( methylamino) -3-nitrophenyl] hexahydro-carbonyl} -3-pyridinyl) carbamic acid 1,1-dimethylethyl Ethyl ester

To (3 R) -3- pyridinyl amino acid hexahydro-1,1-dimethylethyl ester (1.460g, 7.29mmol, commercially available e.g. from Apollo Scientific Ltd.), 4- (dimethylamino) - Add DIPEA (2.55 mL, 14.58) to a solution of 3-nitrobenzoic acid (1.43 g, 7.29 mmol) and HATU (2.77 g, 7.29 mmol) in N,N-dimethylformamide (DMF) (50 mL) The reaction was stirred at rt for 16 h. Water (200 mL) and Et ₂ O (200 mL) were added and the layers were separated. The aqueous layer was further extracted with Et ₂ O ₍₂ × 200mL) and the combined the organics were extracted with water (2 × 50mL), dried (Na ₂ SO ₄₎ and concentrated in vacuo to give a bright yellow oil. The crude product was purified using EtOAc / EtOAc /EtOAcEtOAc Appropriate fractions were combined and evaporated in vacuo to give the product (-(3 R )-1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-hexahydro 1,1-dimethylethyl pyridyl)carbamate (2.76 g, 7.29 mmol, 100% yield).

LCMS (Method B): Rt = 0.96 min, MH ⁺ = 379.3

Intermediate 96: 1,1-dimethylethyl ester of 1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid

1,1-dimethylethyl (+/-60) hexahydropyridylcarbamate (1.460 g, 7.29 mmol, available from, for example, Apollo Scientific Ltd.) and in a manner analogous to Intermediate 95 4-(Methylamino)-3-nitrobenzoic acid was prepared in 57% yield

LCMS (Method B): Rt = 0.96min, MH + = 379.2

Intermediate 97: ( R )-(1-(3-Amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

This intermediate system is made according to one of the following methods A or B:

Method A:

Dissolving ( R )-(1-(4-(methylamino)-3-nitrobenzimidyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (400 mg) in methanol ( Approximately 18 mL) and the solution was hydrogenated on one or two rounds using a flow hydrogenation device (H-Cube, setting: total hydrogen, atmospheric pressure, ambient temperature) on 5% carbon palladium CatCart or 10% palladium on Catcart. The solution was further washed thoroughly with methanol (60 mL) and the solution was reduced to dryness in vacuo to yield ( R )-(1-(3-amino-4-(methylamino)benzhydrazide. Base) tert-butyl hexahydropyridin-3-yl)carbamate (360 mg).

LCMS (Method B): Rt = 0.71min, MH + = 349

Method B:

Ethanol (30mL) in the (R) containing a solution of palladium on carbon (0.400g, 3.76mmol) of hydrogenation flask rinsed - (1- (4- (methylamino) -3-nitrobenzoate acyl Trihydrobutyl-3-hydro)-3-yl)carbamate (2 g, 5.29 mmol), the mixture was washed three times with nitrogen/vacuum, then stirred under hydrogen atmosphere for 44h. The reaction mixture was washed three times with a nitrogen/vacuum from a hydrogen atmosphere and filtered on a pre-filled 10 g of celite (a dark green solution). The appropriate fraction was concentrated under reduced pressure to give 1.95 g of dark green solid. The residue was dissolved in DCM and chromatographed by silicon dioxide MeOH gradient elution with DCM and purified in the 0% to 6% 2M NH ₃ / in 24CV. The relevant fractions were combined and concentrated in vacuo then azeotrope to yield 1.

LCMS (Method A): Rt = 0.85 min, MH ⁺ = 349

Intermediate 98: ( R )-(1-(4-(ethylamino)-3-nitrobenzimidyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

{( 3R )-1-[(4-Chloro-3-nitrophenyl)carbonyl]-3-hexahydropyridyl}aminocarboxylic acid in N,N-dimethylformamide (5 mL) 1,1-Dimethylethyl ester (500 mg, 1.303 mmol) was added 2M ethylamine (5.21 mL, 10.42 mmol) in THF and the mixture was stirred at <RTIgt; After 30 min, additional 2M ethylamine (5.21 mL, 10.42 mmol) eluted The reaction mixture was partitioned between EtOAc EtOAc (EtOAc) The organics were combined, dried using a hydrophobic glass and dried under a stream of nitrogen. The sample was loaded in dichloromethane and purified by Biotage SP4 chromatography (SNAP 100 g EtOAc) using a gradient from 0-100% cyclohexane-ethyl acetate. The appropriate fractions are combined and evaporated in vacuo to give the desired product ( R )-(1-(4-(ethylamino)-3-nitrobenzhydryl) hexahydropyridine-3- Tert-butyl carbamic acid tert-butyl ester (225 mg, 0.573 mmol, 44.0% yield).

LCMS (Method B): Rt = 1.04 min, MH.

Intermediate 99: {(3 R) -1 - [(4 - {[3 - ({[(9 H - fluorenyl-9-ylmethyl) oxy] carbonyl} amino) propyl] amino} - 1,1-dimethylethyl 3-nitrophenyl)carbonyl]-3-hexahydropyridyl}aminocarbamate

( R )-(1-(4-((3-Aminopropyl))amino)-3-nitrobenzimidyl)hexahydropyridine-3-carboxylate under stirring and ice-cooling for 30 min Add chloroformic acid (9H-茀-9- in DCM (10 mL) to a mixture of butyl carbamic acid (2.1 g, 4.98 mmol), DIPEA (1.740 mL, 9.96 mmol) and DCM (20 mL) Methyl ester (1.289 g, 4.98 mmol). The reaction was then stirred under nitrogen at ambient temperature for 15 min. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. The sample was loaded in dichloromethane and used in Biotage SP4 (2 x SNAP 100 g ceria) using a gradient of 0-100% cyclohexane-ethyl acetate in 10 column volumes followed by 100% cyclohexane. Purification was carried out by maintaining a 5-column volume under alkane-ethyl acetate. Appropriate fractions were combined and evaporated under vacuum to give the desired product as a yellow foam. {( 3R )-1-[(4-{[3-({[(9H-茀-9-ylmethyl)))) 1,carbonyl}amino)propyl]amino}-3-nitrophenyl)carbonyl]-3-hexahydropyridyl}aminocarboxylic acid 1,1-dimethylethyl ester (3.09 g, 4.80 mmol , 96% yield).

LCMS (Method B): Rt 1.27 min, MH.

Intermediate 100: ( R )-(1-(4-((3-Aminopropyl)amino)-3-nitrobenzimidyl)hexahydropyridin-3-yl)carbamic acid tert-butyl Base ester

To {(3 R) -1 - [ (4- chloro-3-nitrophenyl) carbonyl] -3-piperidinyl} carbamic acid 1,1-dimethylethyl ester (2g, 5.21mmol Propane-1,3-diamine (10.97 mL, 130 mmol) was added and the mixture was heated at 100 ° C for 1 h while stirring under nitrogen. The reaction mixture was concentrated in vacuo. The sample was then acidified to pH 6 by the addition of 2M hydrochloric acid, dissolved in water (40 mL) and basified to pH 12 using 2M sodium hydroxide. The mixture was then extracted with DCM (3×50 mL). The organics were combined, dried using a hydrophobic glass and evaporated under vacuum to leave ( R )-(1-(4-((3-aminopropyl)amino)-3-nitrobenzhydryl) Hydrogen pyridin-3-yl)carbamic acid tert-butyl ester (2.18 g, 5.17 mmol, 99% yield).

LCMS (Method B): Rt 0.71 min, MH+ 422

Intermediate 101: {(3 R )-1-[(4-{[2-({[(1,1-Dimethylethyl)oxy)carbonyl)amino)ethyl]amino}-3 -nitrophenyl)carbonyl]-3-hexahydropyridyl}aminocarboxylic acid 1,1-dimethylethyl ester

To 1,1-dimethylethyl {( 3R )-1-[(4-chloro-3-nitrophenyl)carbonyl]-3-hexahydropyridyl}carbamic acid (500 mg, 1.30 mmol (2-Aminoethyl)carbamic acid tert-butyl ester (2.06 mL, 13.03 mmol) was added to a solution in 1,4-dioxane (5 mL). After stirring at 100 ° C for 21 h, the reaction mixture was evaporated mjjjjjjjj The residue was loaded onto a 100 g SNAP EtOAc column in DCM and purified eluting with EtOAc EtOAc EtOAc Appropriate fractions were combined and evaporated under reduced pressure to yield the crude product as a dark yellow solid {(3 R) -1 - [ (4 - {[2 - ({[(1,1- dimethylethyl) oxy Carbonyl}amino)ethyl]amino}-3-nitrophenyl)carbonyl]-3-hexahydropyridyl}aminocarboxylic acid 1,1-dimethylethyl ester (682.4 mg, 1.344 mmol, 103% yield). This product was used in the subsequent reaction without further purification.

LCMS (Method B): Rt = 1.06 min, MH ⁺ = 508.3

Intermediate 102: ( R )-(1-(4-Fluoro-3-nitro-5-(trifluoromethyl)benzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

The solution of 4-fluoro-3-nitro-5-(trifluoromethyl)benzoic acid (300 mg, 1.185 mmol, available from, for example, Fluorochem) in DCM (12 mL) was vented 9 times, then the mash was added dropwise. Chlorine (0.208 mL, 2.371 mmol) followed by DMF (0.075 mL, 0.968 mmol). The reaction mixture was initially bubbled. After stirring for 4.5 h under nitrogen, hydrazine chloride (0.052 mL, 0.593 mmol) was added to the reaction mixture, then DMF (18 [mu]L, 0.232 <RTIgt; After stirring at rt for 2 h, the reaction mixture was concentrated under reduced pressure to give a white solid. The residue was dissolved in DCM (12 mL) and EtOAc (EtOAc) &lt;&quot;&quot;&quot;&quot;&&&&&&&&&&&&&&&&&&&&& Mm). After stirring at rt for 18 h, ( R )-trihydropyridin-3-ylaminocarbamic acid tert-butyl ester (119 mg, 0.593 mmol). After stirring at rt for 1 h, EtOAc EtOAc m. The organic layer was washed with sodium bicarbonate (3.times.50 mL), then passed th. The residue was taken up in a pad of EtOAc (EtOAc) EtOAc (EtOAc) Appropriate fractions were combined and evaporated under reduced pressure to give the desired product (R) as a yellow solid - (1- (4-fluoro-3-nitro-5- (trifluoromethyl) benzoyl-yl) hexahydro- Tributyl pyridine-3-yl)carbamate (419 mg, 0.962 mmol, 81% yield).

LCMS (Method A): Rt = 1.21 min, MH ⁺ = 436.0

Intermediate 103: ( R )-(1-(4-(methylamino)-3-nitro-5-(trifluoromethyl)benzylidenyl)hexahydropyridin-3-yl)carbamic acid Third butyl ester

To ( R )-(1-(4-fluoro-3-nitro-5-(trifluoromethyl)benzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (419 mg, Methylamine (1.95 mL of a 2 M solution in THF, 3.85 mmol) was added to a solution. After stirring at 80 ° C for 2 h, the solution was cooled to rt. The reaction mixture was concentrated under reduced pressure and the residue was taken in water (50mL). EtOAc (50 mL) was added and the layers were separated. The aqueous layer was further extracted with EtOAc (4×50 mL). The organic extracts were combined, passed through a hydrophobic glass and the solvent was removed under reduced pressure. The residue was taken up in a pad of EtOAc EtOAc EtOAc (EtOAc). Appropriate fractions were combined and evaporated under reduced pressure to give the desired product (R) as a yellow solid - (1- (4- (methylamino) -3-nitro-5- (trifluoromethyl) benzylamine Tert-butyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester (400 mg, 0.90 mmol, 93% yield).

LCMS (Method A): Rt = 1.15min, MH + = 447.05.

Intermediate 104: 3-methoxy-4-(methylamino)-5-nitrobenzoic acid methyl ester

4-Chloro-3-methoxy-5-nitrobenzoic acid methyl ester (available, for example, from Apollo Scientific Ltd) (14 g, 57.0 mmol) was dissolved in N,N-dimethylformamide (DMF) ( In 140 mL) and cooled to about 0 °C in an ice/water bath. Add methylamine dropwise using a dropping funnel with vigorous stirring (2M in THF) (114 mL, 228 mmol). The mixture was allowed to cool to rt for one week. The reaction mixture was diluted with EtOAc EtOAc m.

LCMS (Method A): Rt = 1.04 min, MH+ = 241.05

Intermediate 105: 3-Methoxy-4-(methylamino)-5-nitrobenzoic acid

To a solution of 3-methoxy-4-(methylamino)-5-nitrobenzoic acid methyl ester (13.69 g, 57.0 mmol) in tetrahydrofuran (THF) (100 mL) and water (50.0 mL) A single portion of lithium hydroxide (4.09 g, 171 mmol) was added. The resulting suspension was stirred at rt for 19 h. The reaction was acidified with 2N aqueous HCl (~ 50 mL) until pH reached ~4. The resulting suspension was filtered and dried with EtOAc EtOAcjjjjjj

LCMS (Method A): Rt = 0.51 min, MH+ = 227.0

Intermediate 106: ( R )-(1-(3-methoxy-4-(methylamino)-5-nitrobenzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl Base ester

To 3-methoxy-4-(methylamino)-5-nitrobenzoic acid (11.09 g, 49.0 mmol) and HATU (18.64 g, 49.0 mmol) in N,N-dimethylformamide DIPEA (17.13 mL, 98 mmol) was added to a solution. Upon addition of DIPEA, the mixture became cloudy after about 1 min of stirring. Then ( R )-trihydropyridin-3-ylaminocarbamic acid tert-butyl ester (9.82 g, 49.0 mmol) was added and stirred for 1.5 h then LCMS showed the reaction was completed. A saturated LiCl aqueous solution (5 mL) and Et ₂ O (10 mL) were added to 5 mL of the reaction mixture, and the layers were separated. The aqueous layer was re-extracted with _{Et 2 O (2 × 10mL)} , the combined organics washed with water (10 mL) trans, dried with Na ₂ SO _4, filtered and concentrated in vacuo to yield the crude product was an orange gum. The gum was dissolved in a minimum of DCM and purified by 50-100% ethyl acetate / cyclohexane over a Si SNAP 25 g column. Appropriate fractions were combined and evaporated in vacuo then dried with EtOAc EtOAc. The remaining reaction mixture was concentrated in vacuo to remove some DMF. A saturated aqueous solution of LiCl (300 mL) and Et ₂ O (700 mL) were added and the mixture was separated. The aqueous layer was re-extracted with _{Et 2 O (2 × 700mL)} , the combined organic layers were washed with water (1L) trans, dried with Na ₂ SO _4, filtered and concentrated in vacuo to yield the crude product was an orange gum. This product was purified by dissolving on 340 g of SNAP ruthenium dioxide column with 30% to 60% ethyl acetate in cyclohexane. The title compound (19.4 g) was obtained.

LCMS: (Method B): Rt = 1.02 min, MH+ = 409.1

Intermediate 107: (1-(3-Methoxy-4-(methylamino)-5-nitrobenzylidenyl)pyrrolidin-3-yl)carbamic acid tert-butyl ester

From 3-methoxy-4-(methylamino)-5-nitrobenzoic acid and pyrrolidin-3-ylaminocarbamic acid tert-butyl ester (purchased from, for example, TCI) in a similar manner to intermediate 106 Europe) Preparation.

LCMS (Method B): Rt = 0.98 min, MH+ = 395.2.

Intermediate 108: 6-(Methylamino)-5-nitronicotinate methyl ester

A solution of 6-chloro-5-nitronicotonic acid methyl ester (500 mg, 2.309 mmol, for example from ButtPark) in anhydrous DMF (2.5 mL) eluted with methylamine (2M in THF, 2.5 mL, 5 mmol) - Instant dark yellow, warming and ppt. The reaction was allowed to stand at ambient temperature (air atmosphere - loosely capped vial) for about 20 min. Additional methylamine (2M in THF, 1.0 mL, 2 mmol) was added and stirring was continued for about 40 min. Most of the solvent was evaporated under a stream of nitrogen and the residue (semi-solid) was diluted with water and treated with DIPEA (~2mL). The mixture was extracted repeatedly with ethyl acetate (solid was especially insoluble in ethyl acetate). The combined organic extracts were dried (hydrophobic glass) and reduced to dryness under nitrogen to give a yellow crystalline solid ( 436 g).

LCMS (Method B): Rt = 0.84 min, MH+=21.21.

Intermediate 109: 1-methyl-2-[1-(phenylmethyl)-1 H -indol-2-yl]-1 H -benzimidazole-5-carboxylic acid methyl ester

To 4-(methylamino)-3-nitrobenzoic acid methyl ester (800 mg, 3.81 mmol) and 1-(phenylmethyl)-1H-indole-2-carbaldehyde under nitrogen at rt ( To a solution of 896 mg, 3.81 mmol) in EtOAc (EtOAc) (EtOAc) The reaction mixture was heated to 80 ° C and stirred overnight. The reaction was cooled to rt. Water (50 mL) and DCM (50 mL) were added, thus an insoluble suspension was obtained, 1N HCl (20 mL) was added and the layers were separated. The aqueous layer was further extracted with 10% MeOH / DCM (2 × 25mL) and the combined organics were diluted with MeOH (20mL), dried (MgSO ₄₎ and concentrated in vacuo to give the crude product as an orange solid. The crude product was purified on a pad of EtOAc (EtOAc) (EtOAc) Appropriate fractions were combined and evaporated in vacuo to give the title compound <RTI ID=0.0>#</RTI><RTIgt; Methyl formate (621 mg, 1.570 mmol, 41.3% yield).

LCMS (Method B): Rt = 1.30 min, MH ⁺ = 396.2

Intermediate 110: 2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

Prepared from 1-ethyl-1H-indole-2-carbaldehyde and 4-(methylamino)-3-nitrobenzoic acid methyl ester (8 g, 38.1 mmol) in a similar manner to Intermediate 109

LCMS (Method B): Rt: 1.20min, MH + 334.

Intermediate 111: 1-Methyl-2-[1-(phenylmethyl)-1 H -indol-2-yl]-1 H -benzimidazole-5-carboxylic acid

Dissolve 1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazole-5-carboxylic acid methyl ester (621 mg, 1.570 mmol) in 1: 1 ratio of tetrahydrofuran (THF) (7.5 mL) and water (7.5 mL). To this was added lithium hydroxide (329 mg, 7.85 mmol). The reaction was stirred at rt for additional 16 h. The reaction mixture was acidified with EtOAc (EtOAc)EtOAc. The aqueous layer was washed with 10% MeOH / DCM (2 × 20mL) and the combined the organics were washed and dried (Na ₂ SO ₄₎ and concentrated in vacuo to give a yellow solid 1-methyl-2- [1- (phenylmethyl Methyl)-1H-indol-2-yl]-1H-benzimidazole-5-carboxylic acid (607 mg, 1.591 mmol, 101% yield). This product was used in the subsequent reaction without further purification.

LCMS (Method B): Rt = 1.13 min, MH ⁺ = 382.2

Intermediate 112: 2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

a solution of 2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (8 g, 24.00 mmol) in THF (50 mL) Lithium hydroxide monohydrate (5 g, 119 mmol) was added, followed by water (50 mL). The mixture was stirred at rt in a stoppered vessel for 16 h. The reaction mixture was then stirred at 80 ° C for 8 h. The reaction mixture was cooled to rt and the volatiles evaporated in vacuo. The remaining small amount of the suspension was acidified to pH = 1 with 2M HCl (aq). The precipitate formed was filtered and the solid was washed with water (400 mL). The solid was dried <RTI ID=0.0>

LCMS (Method ^{B): Rt 1.02min; MH +} 320.

Intermediate 113: 2-(1-Ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

2-Methyl-4-(methylamino)-5-nitrobenzoic acid methyl ester (260 mg, 1.160 mmol), 1-ethyl-1H-indole-2-carbaldehyde (201 mg, 1.160 mmol) Sodium sulfoxylate (606 mg, 3.48 mmol) was combined in EtOAc (3 mL) EtOAc. The reaction mixture was partitioned between EtOAc (EtOAc m. The organics were combined, dried using a hydrophobic glass and evaporated in vacuo. The sample was loaded in methanol/dichloromethane (and the column was dried in a vacuum oven) and purified by EtOAc (EtOAc m. The appropriate fractions were combined and dried under nitrogen to give the desired product 2-(1-ethyl-1H-indole) as a yellow solid. 2-Based-1,6-dimethyl-1H-benzimidazole-5-carboxylic acid methyl ester (249 mg, 0.717 mmol, 61.8% yield).

LCMS (Method B): Rt 1.25 min, MH+ = 348.

Intermediate 114: 2-(1-Ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid

2-(1-Ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzimidazole-5-carboxylic acid methyl ester (245 mg, 0.705 mmol) and lithium hydroxide The hydrate (34 mg) was stirred in MeOH (2 mL) Further lithium hydroxide monohydrate (34 mg) was added and the reaction mixture was heated at 70 ° C for 2.5 days. The reaction mixture was partitioned between EtOAc (EtOAc m. The organics were combined, dried using a hydrophobic glass and dried under a nitrogen stream to give 2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzimidazole-5- Formic acid (242 mg, 0.726 mmol, 103% yield).

LCMS (Method B): Rt 1.05 min.

Intermediate 115: 4-Amino-3-(1-ethyl-1H-indole-2-carboxamido)-5-methylbenzoic acid methyl ester

To 1-ethyl-1H-indole-2-carboxylic acid (358 mg, 1.892 mmol, available from, for example, Enamine building blocks) and HATU (785 mg, 2.064 mmol) in N,N-dimethylformamide (DMF) ( DIPEA (0.901 mL, 5.16 mmol) was added <RTI ID=0.0> Add 3,4-diamino-5-methylbenzoic acid The base ester (310 mg, 1.720 mmol) was stirred for a further 2 h. The reaction mixture was flushed with a pad of EtOAc (EtOAc m.). The appropriate fractions were combined and dried under a stream of nitrogen. The sample was loaded in dichloromethane and purified by Biotage SP4 (SNAP 100 g ceria) using a gradient of 0-10% 2M ammonia in methanol-dichloromethane. The appropriate fractions were combined and evaporated <RTI ID=0.0> Methyl ester (379 mg, 1.079 mmol, 62.7% yield).

LCMS (Method B): Rt 1.10 min, MH+ 352.

Intermediate 116: 2-(1-Ethyl-1H-indol-2-yl)-7-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

4-Amino-3-(1-ethyl-1H-indole-2-carboxamido)-5-methylbenzoic acid methyl ester (375 mg, 1.067 mmol) and p-toluenesulfonic acid monohydrate (223 mg, 1.174 mmol) were combined in toluene (30 mL). The reaction mixture was evaporated under vacuum and the residue was taken in methanol / dichloromethane (and dried in a vacuum oven) and used in a 10-column volume by Biotage SP4 (SNAP 50 g of cerium oxide) 0-100 The % cyclohexane-ethyl acetate gradient was purified by maintaining a 5 column volume under 100% cyclohexane-ethyl acetate. The appropriate fractions were combined and evaporated <RTI ID=0.0></RTI> to <RTI ID=0.0> 5-carboxylic acid methyl ester (105 mg, 0.315 mmol, 29.5% yield).

LCMS (Method B): Rt 1.27 min.

Intermediate 117: 2-(1-Ethyl-1H-indol-2-yl)-1,4-dimethyl-1H-benzo[d]imidazole-6-carboxylic acid

To 2-(1-ethyl-1H-indol-2-yl)-7-methyl-1H-benzo[d]imidazole-5- in N,N-dimethylformamide (1 mL) 60% sodium hydride (18.18 mg, 0.454 mmol) in mineral oil was added to methyl formate (101 mg, 0.303 mmol). The reaction mixture was cooled in ice/water bath and stirred for 90 min. Methyl iodide (0.022 mL, 0.348 mmol) was added and the mixture was warmed to rt and stirred overnight. 60% sodium hydride (18.18 mg, 0.454 mmol) in mineral oil was added followed by iodomethane (0.022 mL, 0.348 mmol) and the mixture was stirred overnight. Lithium hydroxide (14.51 mg, 0.606 mmol) and water (0.5 mL) were added and the mixture was stirred overnight. The reaction mixture was purged under a stream of nitrogen. HATU (173 mg, 0.454 mmol) and N,N-dimethylformamide (1 mL) were added to the obtained solid, then DIPEA (0.159 ml, 0.909 mmol) was added and then stirred at rt for 10 min and then (R)- Tert-butyl hexahydropyridin-3-ylaminocarbamate (91 mg, 0.454 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was flushed with EtOAc (EtOAc) (EtOAc) The organic layers were combined, dried using a hydrophobic glass and dried under a stream of nitrogen. The guanamine was not formed. Instead, the desired carboxylic acid product and its alkylated benzimidazole regioisomer were separated: thus, the residue was dissolved in DMSO (2 x 1 mL) and purified by MDAP (Method B). The solvent was dried under a stream of nitrogen to give the desired product (6 mg) and the product. It is expected that the product will be used in subsequent reactions at this stage without further analysis.

Intermediate 118: 4-bromo-N-methyl-2-nitro-6-(trifluoromethoxy)aniline

4-Bromo-2-nitro-6-(trifluoromethoxy)aniline (1 g, 3.32 mmol, available from eg Apollo Scientific) solution in DMF (40 mL) was cooled with an ice/water bath for 10 min then EtOAc (.. The reaction mixture was stirred for 10 min then EtOAc (EtOAc (EtOAc)EtOAc. Additional iodomethane (0.208 mL, 3.32 mmol) was added and the mixture was stirred for 6h then EtOAc and water. The aqueous layer was re-extracted with EtOAc (EtOAc (EtOAc)EtOAc. The material was purified by EtOAc EtOAc EtOAc EtOAc EtOAc

LCMS (Method A): Rt = 1.33 min, M+NH ₄ ⁺ = 332.7

Intermediate 119: 5-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole

Add a solution of sodium disulfate (780 mg, 3.81 mmol) in water (6.0 mL) and 4-bromo-N-methyl-2-nitro-6-(trifluoromethyl) to a microwave vial equipped with a stirrer A solution of oxy)aniline (400 mg, 1.27 mmol) and 1-ethyl-1H-indole-2-carbaldehyde (220 mg, 1.270 mmol) in EtOH (12 mL). The reaction vessel was sealed and heated to 100 ° C using microwaves for 5 h, then allowed to cool. The reaction mixture was diluted with DCM (40 mL)EtOAc. The crude product was purified using EtOAc EtOAc (EtOAc)

LCMS (Method A): Rt = 1.58 min, MH ⁺ = 438.

Intermediate 120: 2-(1-Ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole-5-carboxylic acid Base ester

5-Bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole in a microwave vial (149 mg, 0.34 mmol), MeOH (0.206 mL, 5.10 mmol), DIPEA (0.119 mL, 0.680 mmol), DMAP (83 mg, 0.680 mmol), hexacarbonyl molybdenum (47 mg, 0.178 mmol) and ethoxylated (2- (Di-o-tolylphosphino)benzyl)palladium (17 mg, 0.018 mmol) was dissolved in 1,4-dioxane (12 mL). The reaction vessel was sealed and heated to 180 ° C using microwaves for 3 h, then allowed to cool. The reaction mixture was concentrated under reduced EtOAcqqqqqqq

LCMS (Method A): Rt = 1.46 min, MH ⁺ = 418.2

Intermediate 121: 2-(1-Ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole-5-carboxylic acid

To 2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester ( Lithium hydroxide (76 mg, 3.19 mmol) was added to a stirred solution of a mixture of THF (12 mL) and water (6 mL). The mixture was stirred at rt under nitrogen for 68 h then filtered over a pad of EtOAc and EtOAc (2N). The reaction mixture was partitioned between EtOAc EtOAc m. The combined organics were passed through a hydrophobic glass and concentrated under reduced pressure to yield crude material. This material was loaded onto a 10 g aminopropyl SPE column in IPA which was eluted with IPA followed by 10% HCl in IPA. The fractions containing the product were combined and concentrated under reduced pressure to give a crude title compound. (121 mg, 28% yield).

LCMS (Method A): Rt = 0.93 min, MH ⁺ = 404.1

Intermediate 122: 7-Bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

To 3-bromo-4-(methylamino)-5-nitrobenzoic acid methylmethyl ester (2.65 g, 9.17 mmol, prepared as described in PCT Int. Appl. WO2010034796A1) and 1-ethyl-1H To a solution of hydrazine-2-carbaldehyde (2.16 g, 12.5 mmol, for example from Sigma Aldrich) in EtOH (70 mL), sodium dithionite (3.4 g, 16.6 mmol) in water (35.0 mL) Solution. The mixture was flushed with nitrogen and then heated at 100 ° C overnight for 16 h. The reaction mixture was concentrated under reduced pressure and then partitioned between DCM (l. After the layers were separated for about 1 h, the organic layer was separated and then aqueous layer was extracted with DCM (3×100mL). The organic layers were combined, dried over sodium sulfate and filtered th The resulting brown solid was purified by EtOAc EtOAcjjjjjj

LCMS (Method B): Rt = 1.40 min, MH ⁺ = 412.0 / 414.0

Intermediate 123: 7-Bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

To 7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (1.97 g, 4.78 mmol) Stir in a mixture of THF (40 mL) and water (20 mL) Lithium hydroxide (229 mg, 9.56 mmol) was added to the suspension. The mixture was stirred at rt for one week then was acidified by EtOAc (2M, 40 mL). The mixture was partitioned with 10% MeOH / 90% DCM (50 mL). The combined organics were dried with EtOAc EtOAc EtOAc.

LCMS (Method B): Rt = 1.20 min, MH ⁺ = 398.0 / 400.1

Intermediate 124: 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

To 4-(methylamino)-3-nitrobenzoic acid methyl ester (6.6 g, 31.4 mmol) and 1-(cyclopropylmethyl)-1 H -indole-2-carbaldehyde (7.0 g, 35.2 mmol) Na ₂ S ₂ O ₄ (16.4 g, 94.2 mmol) was added to a solution in EtOH / H ₂ O (100 mL / 50 mL). The mixture was stirred at 80 ° C under N ₂ overnight and monitored by LCMS. A mixture which showed complete consumption of methyl 4-(methylamino)-3-nitrobenzoate. Water and DCM were added, and the obtained organic phase was dried over Na ₂ SO ₄ and then purified by EtOAc (EtOAc) The title product of this product (7.0 g, 62%)

LCMS (Method D): Rt = 1.78 min, MH ⁺ = 360.2

Intermediate 125: 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

To 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (7.0 g, 195 mmol) LiOH (4.10 g, 975 mmol) was added to a solution of THF / water (150 mL / 150 mL). The mixture was stirred at 50 ° C overnight, then concentrated and water (10 mL). The mixture was neutralized with 2N HCl (50mL), washed with water and filtered and washed with ₂ O Et. Dry solid to give the title compound (5.2 g, 78%)

LCMS (Method D): Rt = 1.62min, MH + = 346.2.

Intermediate 126: 7-Methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d] Imidazole-5-formic acid methyl ester

3-methoxy-4-(methylamino)-5-nitrobenzoic acid methyl ester (235 mg, 0.978 mmol) and 1-(2,2,2-trifluoroethyl) in a 5 mL microwave vial ) -1 H - indole-2-carbaldehyde (200mg, 0.880mmol) in ethanol (3.5 mL of) of the sodium was added (541mg, 2.64mmol) in water (1.5mL) in the suspension. The reaction mixture was heated in a microwave at 100 °C for 5 h. The reaction mixture was concentrated in vacuo. The pale yellow residue was taken up in diethyl ether. The resulting suspension was filtered in vacuo. NMR and LCMS analysis of the collected solid showed the product as a major component. The solid was dried on a vacuum line overnight to give crude product -7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indole as an off-white solid. 2-Base)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (700 mg, 0.755 mmol, 86% yield) which was suitable for the next reaction.

However, LCMS and NMR of the filtrate liquid showed some products and impurities. The filtrate was concentrated in vacuo. The residue was taken up in dichloromethane and purified with EtOAc EtOAc EtOAc. Appropriate fractions were combined and evaporated in vacuo to give the desired product -7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indole as a yellow solid. Indole-2-yl)-1 H -benzo[d]imidazole-5-carboxylic acid methyl ester (49 mg, 0.117 mmol, 13.35% yield).

LCMS (Method B): Rt = 1.29 min, MH ⁺ = 418.1

Intermediate 127: 7-Methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d] Imidazole-5-formic acid

7-Methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1 H -benzo[d]imidazole- A mixture of 5-carboxylic acid methyl ester (318 mg, 0.762 mmol) and lithium hydroxide monohydrate (63.9 mg, 1.524 mmol) in THF (5 mL) (3 mL) LCMS analysis showed no formation of product. Thus, lithium hydroxide monohydrate (63.9 mg, 1.524 mmol) was added and the reaction mixture was stirred for additional 2 h. No product was formed as indicated by LCMS. Therefore, lithium hydroxide monohydrate (128 mg, 3.05 mmol) was further added to the reaction mixture. The reaction mixture was stirred at rt overnight. LCMS analysis indicated that the reaction did not proceed. Therefore, the reaction mixture was concentrated and the residue was taken in water (40 mL). The organics were extracted using DCM (4×40 mL). The aqueous layer was further extracted with a 10% MeOH / DCM solution (3 x 30 mL). The combined collected DCM layer and MeOH/DCM layer were separately concentrated. NMR analysis showed that both DCM and 10% MeOH/DCM batches contained unreacted starting material ester as the main component. The two batches were combined and dried in a vacuum oven for one week.

Re-start the hydrolysis reaction: 7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[ d]A mixture of imidazole-5-formic acid methyl ester (230 mg, 0.551 mmol) and lithium hydroxide monohydrate (46.2 mg, 1.102 mmol) in tetrahydrofuran (THF) (4 mL) and water (3 mL) Overnight for 24h. LCMS analysis indicated the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (7 mL) and 2M EtOAc (aq. The resulting solid was collected by filtration in vacuo, washed with water and then dried in vacuo to give the desired product -7-methoxy-1-methyl-2-(1-(2,2, 2-Trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid (210.5 mg, 0.522 mmol, 68.5% yield).

LCMS (Method B): Rt = 1.13min, MH + = 404.1.

Intermediate 128: 2-(1-Ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

To 3-methoxy-4-(methylamino)-5-nitrobenzoic acid methyl ester (610 mg, 2.54 mmol) and 1-ethyl-1 H -indole in a 10-20 mL microwave vial A solution of sodium sulfoxylate (1.56 g, 7.62 mmol) in water (6 mL). The reaction mixture was heated to 100 ° C for 5 h. The reaction mixture was diluted with DCM (50mL), dried (Na ₂ SO _4), filtered and concentrated in vacuo to afford an off-white solid crude product. The crude product was purified by flash chromatography eluting with EtOAc (EtOAc:EtOAc) The product initially eluted near the solvent front and then tailed through multiple portions, indicating low solubility. Further resolution with 50% (20% MeOH/DCM) / DCM afforded a portion containing product. The appropriate portions of the two columns were combined and concentrated in vacuo to give the product, 2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1- Methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (761 mg, 2.094 mmol, 82% yield).

LCMS (Method B): Rt = 1.26min, MH + = 364.3.

Intermediate 129: 2-(1-Ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

2-(1-Ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (761 mg, 2.094 mmol) Dissolved in a 1:1 ratio of tetrahydrofuran (THF) (12 mL) and water (12 mL). To this was added lithium hydroxide (60.2 mg, 2.51 mmol). LCMS showed only a small amount of conversion. Additional lithium hydroxide (60.2 mg, 2.51 mmol) was added and the mixture was stirred further for 24 h. The reaction proceeds slowly. A further portion of lithium hydroxide (180 mg, 7.53 mmol) was added and the mixture was stirred for additional 24 h. The reaction was still not completed, so a further portion of lithium hydroxide (180 mg, 7.53 mmol) was added and the reaction mixture was stirred for one week - the reaction was now indicated by LCMS. The reaction mixture was acidified (to pH ~5) by addition of 2M EtOAc (~ 20 mL) and organics was taken to 10% MeOH / DCM (20mL). The aqueous layer was washed with 10% MeOH / EtOAc (EtOAc) (EtOAc) -yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (728 mg, 2.084 mmol, 100% yield). This product was used in the subsequent reaction without further purification.

LCMS (Method B): Rt = 1.08 min, MH ⁺ = 350.3.

Intermediate 130: 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid Methyl ester

To 3-methoxy-4-(methylamino)-5-nitrobenzoic acid methyl ester (2.06 g, 8.58 mmol) and 1-(cyclopropylmethyl)-1H-indole-2- A solution of sodium sulfoxylate (5.27 g, 25.7 mmol) in water (32.5 mL) was added to aq. The reaction mixture was heated to reflux for 16 h. The reaction mixture was diluted with DCM (100mL), dried (Na ₂ SO _4), filtered and concentrated in vacuo to give the crude product as an orange solid. The crude product was purified by column chromatography eluting with EtOAc EtOAc EtOAc The product eluted very quickly and then tailed through multiple fractions, indicating poor solubility in the EtOAc/cyclohexane mixture. Appropriate fractions were combined and evaporated in vacuo to give the product as an orange solid which was still imp. The crude product was then purified by column chromatography eluting with EtOAc EtOAc EtOAc. Appropriate fractions were collected and concentrated in vacuo to give the desired product as a solid as a cream, 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1- Base-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (2.185 g, 5.61 mmol, 65.4% yield).

LCMS (Method B): Rt = 1.29min, MH + = 390.1.

Intermediate 131: 2-(1-(Cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

2-(1-(cyclopropylmethyl)-1 H -indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl The ester (2.185 g, 5.61 mmol) was dissolved in 1:1 ratio of tetrahydrofuran (THF) (32 mL) and water (32.0 mL). Anhydrous lithium hydroxide (1.177 g, 28.1 mmol) was added <RTI ID=0.0> The reaction mixture was acidified with EtOAc (EtOAc) (EtOAc) The aqueous layer was washed with 10% MeOH / DCM (2 × 20mL) and the combined the organics were washed and dried (Na ₂ SO ₄₎ and concentrated in vacuo. LCMS confirmed the presence of the product. A large amount of insoluble material is retained in the aqueous layer and this is filtered and the residue analyzed. This is also a pure product by LCMS. The two batches were combined to give the product 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzene as an off white solid. [d] Imidazole-5-carboxylic acid (1.86 g, 4.95 mmol, 88% yield).

LCMS (Method B): Rt = 1.12 min, MH ⁺ = 376.1

Intermediate 132: 1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

To 4-(methylamino)-3-nitrobenzoic acid methyl ester (200 mg, 0.952 mmol) and 1-methyl-1H-indole-2-carbaldehyde (151 mg, 0.952 mmol) under nitrogen at rt. Sodium sulfoxylate (585 mg, 2.85 mmol) dissolved in water (1 mL) was added to a solution of EtOAc (2 mL). The reaction mixture was heated to 80 ° C and stirred overnight. The reaction was cooled to rt. Water (50 mL) and DCM (50 mL) were added and the layers were separated. The aqueous layer was washed with DCM (2 × 25mL) and the combined the organics were extracted further dried (MgSO ₄₎ and concentrated in vacuo to give the crude product as a yellow solid. The crude product was purified by flash chromatography on a SNAP 25g silica gel column using EtOAc EtOAc. Appropriate fractions were combined and evaporated in vacuo to give crystals of <RTI ID=0.0></RTI><RTIgt; Ester (133 mg, 0.416 mmol, 43.8% yield).

LCMS (Method B): rt = 1.12 min.

Intermediate 133: 1-Methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5-carboxylic acid

Dissolving 1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzimidazole-5-carboxylic acid methyl ester (133 mg, 0.416 mmol) in a 1:1 ratio of tetrahydrofuran (THF) (2mL) and water (2 In mL). To this was added lithium hydroxide (87 mg, 2.082 mmol). LCMS showed most of the starting material. The reaction was stirred at rt for additional 16 h. The reaction mixture was acidified with EtOAc (EtOAc)EtOAc. The desired product appeared to be slightly soluble in EtOAc and the layer was taken as a suspension. The aqueous layer was washed with EtOAc (2×20 mL) 2-Base)-1H-benzimidazole-5-carboxylic acid (148 mg, 0.485 mmol, 116% yield). This product was used in the subsequent reaction without further purification.

LCMS (Method B): Rt = 0.94 min, MH+ = 306.1.

Intermediate 134: 7-((Tertibutoxycarbonyl)amino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole -5-methyl formate

Add 7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid to a microwave vial equipped with a septum Base ester (500 mg, 1.213 mmol), butyl butyl carbamate (170 mg, 1.455 mmol), Pd ₂ (dba) ₃ (44.4 mg, 0.049 mmol), Xantphos (112 mg, 0.194 mmol) and cesium carbonate (553 mg) , 1.698 mmol). 1,4-dioxane (5mL) and N ₂ was bubbled through the resulting suspension 2min. The vial was sealed and heated in a microwave at 110 °C for 5 h. By addition of H ₂ O (50mL) quenched the reaction. EtOAc (40 mL) was added and the layers were separated. The aqueous layer was washed with EtOAc (2 × 40mL) and the combined the organics were extracted further dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product as an orange oil. The crude product was purified by flash chromatography on EtOAc EtOAc EtOAc EtOAc. Appropriate fractions were combined and evaporated under vacuum to give the cream foam product - 7-((t-butoxycarbonyl)amino)-2-(1-ethyl-1H-indol-2-yl) 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (398 mg, 0.887 mmol, 73.2% yield).

LCMS (Method B): Rt = 1.27 min, MH+ = 449.3

Intermediate 135: 7 - ((tert-butoxy carbonyl) (methyl) amino) -2- (1-ethyl -1H- indol-2-yl) -1-methyl-benzo -1H- [d]imidazole-5-formic acid methyl ester

To the dry flask was added 7-((t-butoxycarbonyl)amino)-2-(1-ethyl-1H-indole) in N,N-dimethylformamide (DMF) (4 mL) 2-Methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (398 mg, 0.887 mmol) and the reaction mixture was cooled to 0. Sodium hydride (60% dispersion in mineral oil) (39.0 mg, 0.976 mmol) was added and the obtained suspension was stirred at 0 ° C for 30 min and stirred at rt for 30 min. The solution was re-cooled to 0 ° C and iodomethane (0.083 mL, 1.331 mmol). The reaction was allowed to warm to rt and stirred for about 1 h. Additional MeI (40 [mu]L) was added and the reaction was stirred for additional 15 min. An additional portion of NaH (10 mg, 60% dispersion in oil) was added and the mixture was stirred for a further 15 min. By the addition of water (10mL) and the organics extracted the reaction was quenched to Et ₂ O (20mL). The aqueous layer was further extracted with Et ₂ O ₍₂ × 20mL) and then washed the combined organics were washed with water (2 × 20mL) was back extracted. The organic layer was dried (Na ₂ SO ₄₎ and concentrated in vacuo to afford an off-white glassy crude product. The crude product was purified by flash chromatography on EtOAc EtOAc EtOAc EtOAc. The appropriate fractions were combined and evaporated in vacuo to yield white powdery product - 7-((t-butoxycarbonyl)(methyl)amino)-2-(1-ethyl-1H-indole- 2-Based 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (324 mg, 0.700 mmol, 79% yield).

LCMS (Method B): Rt = 1.37 min, MH+ = 463.3

Intermediate 136: 7-((Tertibutoxycarbonyl)(methyl)amino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo [d]imidazole-5-formic acid

To 7-((t-butoxycarbonyl)(methyl)amino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Add lithium hydroxide (17.60 mg, 0.735 mmol) to a stirred suspension of the imidazole-5-carboxylic acid methyl ester (170 mg, 0.368 mmol) in THF (2 mL) / water (1 mL) Stir under overnight. The reaction mixture was acidified with EtOAc (5 mL)EtOAc. The aqueous layer was washed with 10% MeOH / DCM (2 × 10mL) and the combined the organics were washed and dried (Na ₂ SO ₄₎ and concentrated in vacuo to give 7 - ((tert-butoxy carbonyl) (methyl) Amino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (162 mg, 0.361 mmol, 98% yield) .

LCMS (Method B): rt = 1.22 min.

Intermediate 137: 2-(1-Ethyl-1H-indol-2-yl)-1-methyl-7-(methylamino)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester

7-((Tertibutoxycarbonyl)(methyl)amino)-2-(1-ethyl-1H-indol-2-yl)- in methylene chloride (DCM) (2 mL) To a flask of 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (154 mg, 0.333 mmol) was added TFA (0.410 mL, 5.33 mmol) and the mixture was stirred for 30 min. The reaction was stirred for a further 1.5 h. By carefully added to the reaction mixture was stirred NaHCO ₃ solution (50mL) quenched the reaction. DCM (30 mL) was added and the layers were separated. The aqueous layer was washed with DCM (2 × 30mL) and the combined the organics were extracted further dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product as a white solid. The crude product was purified by EtOAc (EtOAc) eluting eluting Appropriate fractions were combined and evaporated in vacuo to give the crude product as a solid, 2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(methylamino)-1H -Benzo[d]imidazole-5-carboxylic acid methyl ester (120 mg, 0.331 mmol, 99% yield).

LCMS (Method B): rt = 1.13 min.

Intermediate 138: 7-(Dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid Base ester

A stock solution of MeI (58 [mu]L, 0.93 mmol) in DMF (1 mL) was obtained in a dry flask. To the second dry flask was added 2-(1-ethyl-1H-indol-2-yl)-1-methyl in N,N-dimethylformamide (DMF) (0.7 mL) at rt. Methyl-7-(methylamino)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (30.5 mg, 0.084 mmol). Sodium hydride (60% dispersion in mineral oil) (6.73 mg, 0.168 mmol) was added and the resulting orange solution was stirred at rt for 20 min. An aliquot of the MeI stock solution (100 μL, 0.093 mmol) was added and the reaction mixture was stirred for 1 h. An aliquot of the MeI stock solution (20 μL) was added and the reaction mixture was stirred for a further 30 min. A small amount of NaH (2 mg) was added and the mixture was stirred for 1 h. By the addition of water (10mL) and the organics extracted the reaction was quenched to Et ₂ O (20mL). The aqueous layer was further extracted with Et ₂ O ₍₂ × 20mL) and then washed the combined organics were washed with water (2 × 20mL) was back extracted. The organic layer was dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product as a white solid. This was combined with a second batch of identical compounds from different experiments for purification: 5% EtOAc/cyclohexane->60% ethyl acetate/cyclohexane on a SNAP 10 g cerium oxide column by Biotage SP4 flash chromatography. A gradient of the alkane was used to purify the combined crude product. Appropriate fractions were combined and evaporated in vacuo to give the desired product -7-(dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H -Benzo[d]imidazole-5-carboxylic acid methyl ester (38 mg, 0.101 mmol). Yield based on two reactions = 67%.

LCMS (Method B): Rt = 1.32 min, MH+ = 377.2.

Intermediate 139: 7-(Dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

To 7-(dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester ( To a stirred suspension of tetrahydrofuran (THF) (1 mL) / EtOAc (EtOAc) (EtOAc) The reaction mixture was then allowed to stand for 72 h during which time some of the THF evaporated. 2M HCl (aq.) (10 mL) and 10% MeOH / DCM (10 mL). The aqueous layer was further extracted with 10% MeOH / DCM (2 x 20 mL). The combined organics were dried (Na ₂ SO ₄₎ and concentrated in vacuo. LCMS showed only 30% production and 70% SM. The crude product was redissolved in tetrahydrofuran (THF) (1 mL) / water (0.5 mL). The reaction was stirred overnight and then LCMS showed only 7% SM remained. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc) The combined organics were dried (Na ₂ SO ₄₎ and concentrated in vacuo to afford a pale yellow solid 7- (dimethylamino) -2- (1-ethyl-indole-2 -1H- 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (48 mg, 0.132 mmol, 102% yield).

LCMS (Method B): rt = 1.13 min.

Intermediate 140: 2-(1-Ethyl-1H-indol-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester

6-(Methylamino)-5-nitro-3-picolinic acid methyl ester (400 mg, 1.894 mmol) and 1-ethyl-1H-indole-2-carbaldehyde (328 mg, 1.894 mmol) were suspended in In ethanol (4.0 mL). The suspension was treated with sodium sulfite (1.16 g, 5.66 mmol) and water (2.0 mL). The reaction was cooled and partitioned between water and DCM. The aqueous layer was extracted with DCM (×2). The combined organic extracts were dried (hydrophobic glass) and reduced to dryness under a nitrogen stream to yield crude product as an orange oil. This product was triturated with diethyl ether and the solid was isolated by filtration (still viscous). The solid was reground with ethyl acetate. All three fractions (ether solution, solid and ethyl acetate solution) contained the desired product by LCMS. Therefore, the fractions were dissolved in ethyl acetate/acetone and absorbed onto cerium oxide in vacuo. The cerium oxide was applied to a 1 x 20 g cerium oxide column and eluted with a gradient of ethyl acetate / cyclohexane (0-16%). The product fractions were combined and reduced to dryness in vacuo to give a desired product (l.

LCMS (Method B): rt = 1.21. min.

Intermediate 141: 2-(1-Ethyl-1H-indol-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, lithium salt

3-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-3H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester (275 mg, 0.822 mmol) and lithium hydroxide. H ₂ O (20 mg, 0.477 mmol) were combined in THF (10.0 mL) and water (3.0 mL), and the resulting suspension was stirred at ambient temperature (air atmosphere) for about 4 h. LCMS 50% reaction - no change from 2.5 h sample. A further portion of lithium hydroxide.H ₂ O (20 mg, 0.477 mmol) was added and stirring was continued for ca. 2 h (87% by LCMS). The solvent was evaporated under EtOAc (EtOAc m.

LCMS (Method B): Rt = 1.02 min.

Intermediate 142: [(3 R )-1-({2-[1-ethyl-6-(methyloxy)-1 H -indol-2-yl]-1-methyl-1 H - 1,1-dimethylethyl ester of benzimidazol-5-yl}carbonyl)-3-hexahydropyridyl]carbamic acid

Add HATU to a solution of 1-ethyl-6-methoxy-1H-indole-2-carboxylic acid (201.8 mg, 0.792 mmol) in N,N-dimethylformamide (DMF) (5 mL) (860 mg, 1.397 mmol) and stirred at rt for 5 min. DIPEA (0.41 mL, 2.354 mmol) and ( R )-(1-(3-amino-4-(methylamino)benzylidene)hexahydropyridin-3-yl)amine were added to the reaction mixture. A solution of tert-butyl formate (457.5 mg, 1.113 mmol) in EtOAc (EtOAc) (EtOAc) ( R )-(1-(3-Amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (148.3 mg) was added to the reaction mixture. And stirred under nitrogen at rt for 2 h. DIPEA (0.5 mL) was added and the mixture was stirred at rt. The reaction mixture was stirred at rt under EtOAc overnight. Distilled water (40 mL) was added to the reaction mixture and the organic product was extracted with Et ₂ O (40 mL) and the layers were separated. The aqueous layer was further extracted with Et ₂ O (2×40 mL). The organic layer was collected and back extracted using water (2×30 mL). The organic layer was collected, dried Na ₂ SO _4, dried, and concentrated under vacuum it passed through a hydrophobic frit to yield a blue solid. The blue solid was dried under high vacuum overnight to afford the desired guanamine intermediate.

LCMS (Method A) Rt = 1.20 min, MH ⁺ = 550.3.

The guanamine intermediate was dissolved in toluene (10 mL). Acetic acid (0.04 mL, 0.699 mmol) was added to the solution and refluxed for 1.5 h. Sodium bicarbonate (40 mL) was added to the reaction mixture and the layers were separated. The aqueous layer was further extracted with toluene (3 x 30 mL). The organic layer was collected, dried over Na ₂ SO _4, passed through a hydrophobic frit and concentrated in vacuo. The product was purified on cerium oxide (25 g). The column was eluted with a gradient of 60-100% ethyl acetate / cyclohexane. The appropriate fractions were collected and concentrated in vacuo to give -[(3 R )-1-({2-[1-ethyl-6-(methyloxy)-1 H -indol-2-yl]- 1,1-Dimethylethyl 1-methyl- 1H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinyl]carbamate (102 mg, 24%).

LCMS (Method B): Rt = 1.10 min, MH ⁺ = 532.3

Intermediate 143: ( R )-(1-(2-(6-Ethoxy-1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 3-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

From 6-ethoxy-1-ethyl-1H-indole-2-carboxylic acid and ( R )-(1-(3-amino-4-(methylamino)) in a similar manner to intermediate 142 Preparation of benzhydryl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 1.17 min, MH+ = 546.4

Intermediate 144: ((3 R )-1-{[2-(1-ethyl-6-fluoro-1 H -indol-2-yl)-1-methyl-1 H -benzimidazole-5 -yl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1-dimethylethyl ester

In a manner similar to the intermediate 142, from 1-ethyl-6-fluoro-1H-indole-2-carboxylic acid and ( R )-(1-(3-amino-4-(methylamino)phenyl) Preparation of decyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method A): Rt = 1.23 min, MH ⁺ = 520.2

Intermediate 145: [(3 S )-1-({1-methyl-2-[1-(phenylmethyl)-1 H -indol-2-yl]-1 H -benzimidazole-5 -yl}carbonyl)-3-hexahydropyridinyl]1,1-dimethylethyl carbamic acid

To the ( S )-hexahydropyridin-3-ylaminocarbamic acid tert-butyl ester (47.3 mg, 0.236 mmol, available from, for example, Sigma-Aldrich), 1-methyl-2-[1-(phenylmethyl) -1H-indol-2-yl]-1H-benzimidazole-5-carboxylic acid (90 mg, 0.236 mmol) and HATU (90 mg, 0.236 mmol) in N,N-dimethylformamide (DMF) ( DIPEA (0.082 mL, 0.472 mmol) was added <RTI ID=0.0> Water (20 mL) and EtOAc (20 mL) were added and the layers were separated. The aqueous layer was further extracted with EtOAc (2 × 20mL) and the combined the organics were extracted with water (2 × 20mL), dried (MgSO ₄₎ and concentrated in vacuo to give a yellow oil. The crude product was purified using a gradient of 40% EtOAc / cyclohexane - &gt; 100% ethyl acetate / cyclohexane over EtOAc. Appropriate fractions were combined and evaporated in vacuo to give the product as a yellow oil -[( 3S )-1-({1-methyl-2-[1-(phenylmethyl)-1H-indole-2- 1,1-H-ethylethyl ester of 1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinyl]carbamate (115 mg, 0.204 mmol, 86% yield).

LCMS (Method B): Rt = 1.25 min, MH ⁺ = 564.3

Other examples indicated in the table below were prepared in a manner similar to Intermediate 145:

Intermediate 156: ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzo[d]imidazole-5-carbonyl ) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 145 from 2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid and ( R Preparation of tert-butyl hexahydropyridin-3-ylaminocarbamate.

LCMS (Method B): Rt 1.15 min, MH ⁺ = 516.4

Intermediate 157: {2-[({1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl}carbonyl)amine 1,1-dimethylethyl ester of ethyl}aminocarbamate

From 1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazole-5-carboxylic acid and (2-amine) in a similar manner to Intermediate 145 Preparation of 1,1-dimethylethyl carbamoylcarbamate (available, for example, from Sigma-Aldrich)

LCMS (Method B): Rt 1.20 min, MH ⁺ 524

Intermediate 158: ((3 S ,4 R )-4-hydroxy-1-(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H -non-2-yl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

From 7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1 H -indol-2-yl)-1H in a similar manner to the intermediate 145 Preparation of benzo[d]imidazol-5-carboxylic acid and ((3 S ,4 R )-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt = 1.15min, MH + = 602.5.

Intermediate 159: ((3 S ,4 R )-1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 145 from 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and ((3 S, 4 R) -4- hydroxy-hexahydro-3-yl) carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 1.07 min, MH ⁺ = 544.2

Intermediate 160: ((3 S ,4 R )-1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl- 1H-benzo[d]imidazol-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 145 from 2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d] Preparation of imidazole-5-carboxylic acid and (3S,4R)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 1.13 min, MH+ = 574.2

Intermediate 161: ((3 S ,4 R )-1-(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[ d]imidazole-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 145 from 2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid And (3S,4R)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester was prepared.

LCMS (Method B): Rt = 1.09 min, MH+ = 548.4

Intermediate 162: ((3 R ,4 S )-4-hydroxy-1-(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H -吲哚-2-yl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

From the same manner as the intermediate 145 from 7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)-1H- Preparation of benzo[d]imidazol-5-carboxylic acid and (4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 1.15 min, MH ⁺ = 602.5

Intermediate 163: ( S )-(1-(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-carbonyl)hexahydro Pyridin-3-yl)carbamic acid tert-butyl ester

In a similar manner to the intermediate 145 from ( S )-3-(Boc-amino)-hexahydropyridine (available from, for example, Acros Organics) and 1-methyl-2-(1-methyl-1H-indole Preparation of 2-yl)-1H-benzimidazole-5-carboxylic acid.

LCMS (Method B): Rt = 1.08 min, MH+ = 488.4

Intermediate 164: ( R )-(1-(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5-carbonyl)hexahydro Pyridin-3-yl)carbamic acid tert-butyl ester

In the similar manner as Intermediate 145 from (3 R) -3- pyridinyl hexahydro-1,1-dimethylethyl carbamic acid ester (e.g. commercially available from Apollo Scientific) and 1-methyl-2- (1 Preparation of -methyl-1H-indol-2-yl)-1H-benzimidazole-5-carboxylic acid.

LCMS (Method B): Rt = 1.04 min, MH+ = 488.4

Intermediate 165: (3-(2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)cyclopentyl)amine Tert-butyl formate.

In a manner similar to the intermediate 145 from 1,1-dimethylethyl 3-pyrrolidylcarbamate (available from, for example, Sigma-Aldrich) and 1-methyl-2-[1-(phenyl-phenyl) Preparation of -1H-indol-2-yl]-1H-benzimidazole-5-carboxylic acid.

LCMS (Method B): rt = 1.22 min.

Intermediate 166: ( R )-(5-(3-((T-butoxycarbonyl)amino)hexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indole-2- Benzyl-1-methyl-1H-benzo[d]imidazol-7-yl)(methyl)aminocarbamic acid tert-butyl ester

From 7-((t-butoxycarbonyl)(methyl)amino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl in a similar manner to the intermediate 145 -1H-Benzo[d]imidazole-5-carboxylic acid and ( R )-hexahydropyridin-3-ylaminocarbamic acid tert-butyl ester (available, for example, from Apollo Scientific).

LCMS (Method B): Rt = 1.30 min, MH+ = 631.5

Intermediate 167: ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridine-6- Carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

Lithium salt of 2-(1-ethyl-1H-indol-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate in a similar manner to Intermediate 145 And ( R )-trihydropyridin-3-ylaminocarbamic acid tert-butyl ester (available, for example, from Apollo Scientific).

LCMS (Method B): rt = 1.16 min.

Intermediate 168: ( R )-(1-(7-(Dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[ d] imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

From 7-(dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in a similar manner to the intermediate 145 -5-Formic acid and ( R )-hexahydropyridin-3-ylaminocarbamic acid tert-butyl ester (available, for example, from Apollo Scientific).

LCMS (Method B): rt = 1.25 min.

Intermediate 169: ( R )-(1-(7-Bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5- Carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 145 from 7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid and ( Preparation of R )-trihydropyridin-3-ylaminocarbamic acid tert-butyl ester.

LCMS (Method B): Rt = 1.32 min, MH ⁺ = 580.3/582.3

Intermediate 170: ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[ d] imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

From 2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethoxy)-1H-benzo[d]imidazole in a similar manner to the intermediate 145 Preparation of -5-carboxylic acid and ( R )-hexahydropyridin-3-ylaminocarbamic acid tert-butyl ester.

LCMS (Method A): Rt = 1.40min, MH + = 586.4

Intermediate 171: ((3 R )-1-{[2-(6-Cyano-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazole- 1,1-dimethylethyl 5-phenyl]carbonyl}-3-hexahydropyridyl)carbamate

In a dry 2 mL microwave vial under nitrogen to ( R )-(1-(2-(6-bromo-1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[ d]imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (50.2 mg, 0.086 mmol) in N,N-dimethylformamide (DMF) (1 mL) Zinc cyanide (9.1 mg, 0.078 mmol) was added to the stirred solution and stirred for 20 min. Tetra-palladium (5.6 mg, 4.85 μmol) was added to the reaction mixture and the vial was heated in a microwave for 1 h at 95 °C. The reaction mixture was heated to 105 ° C in the microwave for 1 h. Further zinc cyanide (10.5 mg) was added to the reaction mixture and this was stirred under nitrogen for 15 min. Tetrapalladium (10.2 mg) was added and the reaction was heated in a microwave at 95 °C.

The reaction was reheated to 95 ° C in the microwave and held for an additional 2 h. The reaction mixture was poured into saturated aqueous Na ₂ CO ₃ (50mL) and extracted with EtOAc (50mL). The aqueous layer was further extracted with EtOAc (2×50 mL). The combined organic portions were washed with water (50 mL) then brine (50 mL). The washed organic portion was dried over Na ₂ SO ₄ and passed through a hydrophobic glass. The combined organics were concentrated in vacuo to yield a yellow oil. The crude product was purified on cerium oxide (25 g). The column was eluted with a gradient of 50-100% ethyl acetate / cyclohexane. Appropriate fractions were collected and concentrated under vacuum to give the desired product as two crops which were still impure. These products were further purified using MDAP (Method A). The product fractions were collected and concentrated in vacuo to give (( 3R )-1-{[2-(6-cyano-1-ethyl- 1H -indol-2-yl)-1-methyl- 1,1-dimethylethyl 1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridyl)carbamate (19.2 mg, 42%) which was still impure and was Used for subsequent reactions.

LCMS (Method B): Rt = 1.12 min, MH ⁺ = 527.3

Intermediate 172: N , N '-((3,4- cis )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H - Benzimidazol-5-yl]carbonyl}-3,4-hexahydropyridinyl) bis( 2,2,2-trifluoroacetamide)

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (200 mg, 0.626 mmol) and HATU (238 mg, 0.626 mmol) DIPEA (0.547 mL, 3.13 mmol) was added <RTI ID=0.0></RTI> Add N,N'-(hexahydropyridine-3,4-diyl) bis( 2,2,2-trifluoroacetamide) in N,N-dimethylformamide (DMF) (2 mL) Acetate (402 mg, 1.096 mmol) and the mixture was stirred at rt for 1 h. The reaction was stirred overnight. Water (50 mL) and Et ₂ O (50 mL) were added and the layers were separated. The aqueous layer was further extracted with Et ₂ O ₍₂ × 30mL) and the combined the organics were extracted with water (2 × 20mL), dried (Na ₂ SO ₄₎ and concentrated in vacuo to give a brown oil. The crude product was purified using EtOAc / EtOAc /EtOAc. A certain separation of the non-image isomers was observed. Three groups were collected and partially concentrated in vacuo to give: trans - diastereomers (rac) - (20.4mg, 5%) ; diastereomeric mixture - (119mg, 31%); cis - Non-image isomer (racemic) - (55.3 mg, 14%).

An unseparated mixture of non-image isomers (119 mg) was used for preparative chiral HPLC (Method E) to resolve the four components. This gives: N,N'-((3,4 -trans )-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazole-5-carbonyl)hexahydropyridine-3,4-diyl)bis(2,2,2-trifluoroacetamide) (11 mg, 0.018 mmol, 2.89% yield); Trans- non-image isomer; chiral HPLC (method D): Rt = 6.55 min.

N,N'-((3,4 -trans )-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5- carbonyl) hexahydro-pyridine-3,4-diyl) bis (2,2,2-trifluoroethyl as acetamide) (10mg, 0.016mmol, 2.62% yield); single enantiomer, trans - Non-image isomer; chiral HPLC (method D): Rt = 8.58 min.

N,N'-((3,4-cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5-carbonyl) hexahydropyridine-3,4-diyl) bis(2,2,2-trifluoroacetamide) (37 mg, 0.061 mmol, 9.71% yield); single-image isomer, cis- Non-image isomer; chiral HPLC (method D): Rt = 14.24 min.

N,N'-((3,4-cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5-carbonyl) hexahydropyridine-3,4-diyl) bis(2,2,2-trifluoroacetamide) (37 mg, 0.061 mmol, 9.71% yield); single-image isomer, cis- Non-imagewise isomer; Chiral HPLC (Method D): Rt = 23.14 min.

Intermediates 173 and 174: ((cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl a tert-butyl-6-methylhexahydropyridin-3-yl)carbamate having a single unknown mirror image isomer of known relative stereochemistry

(6-Methylhexahydropyridin-3-yl)carbamic acid tert-butyl ester (512 mg, 2.389 mmol, purchased from, for example, ISPharm) in N,N-dimethylformamide (DMF) (10 mL) And 2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (763 mg, 2.289 mmol) was added HATU (908 mg, 2.389) mmol) and Et ₃ N (0.666mL, 4.78mmol) and the reaction was stirred at ambient temperature for 48h. The reaction was then heated in a microwave at 60 °C for 1 h. Additional HATU (908 mg, 2.389 mmol) was then added and the reaction was microwaved at 60 °C for 1 h then microwaved at 100 °C for 1 h. The reaction mixture was partitioned between DCM and water (×3) and the combined organics were washed with water and then evaporated. The residue was redissolved in DCM and loaded onto a 25 g EtOAc SNAP column and purified on EtOAc EtOAc EtOAc After evaporation, the material was subjected to additional purification by MDAP (Method B). Combine the appropriate parts and remove the solvent. The residue was dried under high vacuum overnight to give a yellow crystal which was subsequently purified eluted elute

Intermediate 173: LCMS (Method B): m.

Intermediate 174: <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI>

Intermediate 175: 3-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxamido Azacycloheptane-1-carboxylic acid tert-butyl ester

2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzene in N,N-dimethylformamide (DMF) (6 mL) And [d]imidazole-5-carboxylic acid (200 mg, 0.579 mmol) was added with 3-aminoazepane-1-carboxylic acid tert-butyl ester (124 mg, 0.579 mmol, available from, for example, J&W Pharmlab) and HATU ( 264mg, 0.695mmol) and Et ₃ N (0.242mL, 1.737mmol) and the reaction was stirred over a weekend at rt. Addition of additional 3-aminoazepane-1-carboxylic acid tert-butyl ester (50 mg, 0.23 mmol), Et ₃ N (0.2 mL, 1.44 mmol) and HATU (200 mg, 0.53 mmol) 4h. The reaction mixture was partitioned between DCM and water (×3), then the combined organic layer was washed with water (×2) and solvent was removed. The residue was dissolved in DCM and loaded onto a 25 g s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Appropriate fractions were combined and the solvent removed to give a clear crystal residue (123 mg, 39%).

LCMS (Method B): Rt = 0.84 min, MH+ = 442.3.

Intermediate 176: N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-5-A Hexahydropyridin-3-yl)-2,2,2-trifluoroacetamide, a mixture of non-image isomers

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (6 mL) 5-carboxylic acid (185mg, 0.579mmol) was added HATU (264mg, 0.695mmol) and _{Et 3 N (0.404mL, 2.90mmol)} , after addition of 2,2,2-trifluoro -N- (5- methylhexahydrophthalic Hydropyridin-3-yl)acetamide acetate (220 mg, 0.814 mmol). Additional Et ₃ N (1 mL) and 2,2,2-trifluoro-N-(5-methylhexahydropyridin-3-yl)acetamide (220 mg, 1.047 mmol) in DMF (1 mL) The reaction was stirred for 1 h. Additional HATU (264 mg, 0.695 mmol) was added and the mixture was stirred for 90 min. 2,2,2-Trifluoro-N-(5-methylhexahydropyridin-3-yl)acetamide (about 100 mg) was then added and the reaction was taken overnight. The solvent was removed and the residue was dried under high vacuum for 1 h. Was added _{HATU (1g), Et 3 N} (1mL) and DMF (6mL) and the reaction was stirred overnight. Water was added and the organics were extracted into DCM (×3). The combined organic layers were washed with water and the solvent was removed. The residue was dissolved in DCM and purified using EtOAc EtOAc EtOAc. The appropriate fractions were combined with EtOAcqqqqm

LCMS (Method B): rt = 1.14 min.

Intermediate 177: N- (1- (2- ( 1- ethyl--1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazol-5-yl-carbonyl) -5-fluoro Hexahydropyridin-3-yl)-2,2,2-trifluoroacetamide, a mixture of non-image isomers

To 2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (12 mL) 5-carboxylic acid (522mg, 1.636mmol) was added HATU (745mg, 1.961mmol) and _{Et 3 N (1.139mL, 8.20mmol)} . Reaction for 15 min. 2,2,2-Trifluoro-N-(5-fluorohexahydropyridin-3-yl)acetamide acetate (567 mg, 2.07 mmol) was then added and the mixture was stirred at rt overnight under nitrogen. Water was added and the mixture was partitioned between DCM and water (x3). The combined organic layers were evaporated to give a beige solid which was dissolved in DCM / MeOH and loaded onto cerium oxide and dried in a vacuum oven for 1 h, then eluted with 0-100% ethyl acetate in cyclohexane. . Appropriate fractions were combined and the solvent was removed to give a beige solid which was suspended in methanol (2mL) and filtered. The liquid was purified by MDAP (Method B) - mp EtOAc (EtOAc)

LCMS (Method B): rt = 1.10 min.

Intermediate 178: cis- N,N'-(-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 -carbonyl)hexahydropyridine-3,5-diyl) bis( 2,2,2-trifluoroacetamide)

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (6 mL) 5-carboxylic acid (0.870g, 2.72mmol) was added HATU (1.242g, 3.27mmol) and Et ₃ N (1.898mL, 13.61mmol) and the reaction was stirred for 1h. N,N'-(Hexahydropyridine-3,5-diyl) bis( 2,2,2-trifluoroacetamide) acetate (1 g, 2.72 mmol) was added and the mixture was stirred overnight. The solution was partitioned between DCM and water (×3), and the combined organic layers were washed with water (×2) and solvent was removed. The crude product was purified by chromatography on EtOAc over EtOAc (EtOAc) The appropriate fractions were combined with EtOAcqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ

LCMS (Method B): rt = 1.11 min.

Intermediate 179: (+/-) - N - (( trans) -1- (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d Imidazole-5-carbonyl)-5-methoxyhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (6 mL) 5-carboxylic acid (1116mg, 3.49mmol) was added HATU (1594mg, 4.19mmol), and Et ₃ N (2.435mL, 17.47mmol) and the reaction was stirred for 1h. 2,2,2-Trifluoro-N-(5-methoxyhexahydropyridin-3-yl)acetamide acetate (1000 mg, 3.49 mmol) was added and the mixture was stirred overnight. The residue was partitioned between DCM and water (×3) and the combined organic layer was washed with water (×2). The solvent was removed and the residue was taken up in DCM and taken to EtOAc (EtOAc) Combine the appropriate parts and remove the solvent. Further purification was achieved by MDAP (Method B). Combine the appropriate parts and remove the solvent. The residue was dried under high vacuum overnight to afford product (yield: 13 mg, 1%)

LCMS (Method B): Rt = 1.05 min.

Intermediate 180: N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-hydroxyl Hexahydropyridin-3-yl)-2,2,2-trifluoroacetamide

Prepared as a by-product (6 mg, 0.3%) in the preparation of intermediate 179.

LCMS (Method B): rt = 0.99 min.

Intermediate 181: (+/-)- N -((cis)-1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo [d]imidazole-5-carbonyl)-5-methylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (6 mL) -5-carboxylic acid (98 mg, 0.307 mmol) and 2,2,2-trifluoro-N-((cis)-5-methylpyrrolidin-3-yl)acetamilide trifluoroacetate (60 mg, 0.193) mmol) was added HATU (140mg, 0.368mmol) and Et ₃ N (0.128mL, 0.919mmol) and the reaction was stirred over a weekend under nitrogen. The reaction was then partitioned between DCM and water (×3) and the combined organic layers were washed with water (×2) and solvent was removed. The residue was dissolved in DCM and loaded onto a 10 g s s s s s s s s s s s s s s s s s s s s s s s s s s s Appropriate fractions were combined, the solvent was removed and the residue was dried <RTI ID=0.0>

LCMS (Method B): Rt = 1.07 min.

Intermediate 182 and intermediate 183: N -(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) 4-methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide trans and cis isomer

A solution of 2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (400 mg, 1.25 mmol) in DMF (3 mL) T3P (1.12 mL, 1.88 mmol, 50% in ethyl acetate) and DIPEA (0.436 mL, 2.51 mmol). After 5 min, 2,2,2-trifluoro-N-(4-methylhexahydropyridin-3-yl)acetamide (263 mg, 1.25 mmol) was obtained. 1 equivalent of T3P (0.746 mL, 1.25 mmol, 50% in ethyl acetate) and DIPEA (0.218 mL, 1.25 mmol). T3P and DIPEA were added twice in succession and the reaction was stopped after 48 h. The reaction mixture was partitioned between water and ethyl acetate. The organics were combined, passed through a pad of water and concentrated in vacuo. The residue was purified by Biotage SP4 chromatography on a 25 g cerium oxide SNAP column eluting with 0 to 3% methanol in DCM in 20 column volumes.

Combine the earlier fractions and concentrate under vacuum to give N- (1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5-carbonyl)-4-methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide:

Intermediate 182: trans- isomer (143 mg, 22%).

LCMS (Method B): Rt 1.12min, m / z 512.2 (MH +).

The later fractions were combined and concentrated under vacuum to give N- (1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5-carbonyl)-4-methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide.

Intermediate 183: cis- isomer as a yellow oil (524 mg, 82%).

LCMS (Method B): Rt 1.14min, m / z 512.2 (MH +).

Intermediate 184: 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-(2,2 , 2-trifluoroacetamido) hexahydropyridine-3-carboxylic acid methyl ester

From 5-(2,2,2-trifluoroethylamino)hexahydropyridine-3-carboxylic acid methyl ester and 2-(1-ethyl-1H-indole-2 in a similar manner to intermediate 182 Preparation of -yl)-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid.

LCMS (Method B): Rt = 1.09 min, MH ⁺ = 556.2

Intermediate 185: (+/-) - 1- (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazol-5-carbonyl) - 5-(2,2,2-Trifluoroethylamino)hexahydropyridine-3-carboxylic acid, cis- isomer.

1-(2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-(2, at 40 ° C 2,2-Trifluoroacetamido) hexahydropyridine-3-carboxylic acid methyl ester (mixture of non-image isomers) (1.61 g, 2.90 mmol) in tetrahydrofuran (10 mL) and water (5 mL) with hydrogen Lithium oxide (0.083 g, 3.48 mmol) was stirred together for 70 h. The mixture was concentrated in vacuo and chromatographed by biotage SP4 100g silica gel with DCM and SNAP column of 0 to 20% 2M NH ₃ / MeOH in 20 column volumes, followed by the use of DCM to 20% 2M NH ₃ / MeOH in 10 column volumes elution residue was purified, to afford a colorless oil desired cis - product (237mg.15%).

LCMS (Method B): Rt 1.00min, m / z 542.2 (MH +)

Intermediate 186: (+/-)- cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5- Carbonyl)-5-(2,2,2-trifluoroethylamino)hexahydropyridine-3-carboxamide.

Cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-5-(2,2 , 2-trifluoroacetamido) hexahydropyridine-3-carboxylic acid (230 mg, 0.425 mmol) in 1,4-dioxane (3 ml) and T3P (0.506 mL, 0.85 mmol, 50% in ethyl acetate DIPEA (0.222 mL, 1.274 mmol) and ammonia (2.55 mL, 1.27 mmol, 0.5 M in 1,4-dioxane) were added to the suspension. The resulting mixture was stirred at 70 &lt;0&gt;C for 2 h then additional EtOAc EtOAc (EtOAc &lt After 1 h, DIPEA and T3P were added repeatedly and reacted at 70 ° C for 20 h. The reaction was cooled and the mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate. The organics were combined, washed with brine, dried over EtOAc EtOAc. 25g Biotage SP4 by silica gel chromatography with DCM and SNAP column of 0 to 20% 2M NH ₃ / MeOH in 15 column volumes, followed by the use of DCM to 20% 2M NH ₃ / MeOH in the column volume of 5 The residue was purified by EtOAc (EtOAc:EtOAc)

LCMS (Method B): Rt 0.95min, m / z 541.3 (MH +)

Intermediate 187: cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-3-( 2,2,2-trifluoroacetamido) hexahydropyridine-4-carboxylic acid methyl ester, single unknown mirror image isomer

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (10 mL) 5-carboxylic acid (900mg, 2.821mmol) was added HATU (1286mg, 3.384mmol) and _{Et 3 N (1.964mL, 14.1mmol)} . The reaction was stirred for 15 min. Add 3-(2,2,2-trifluoroacetamido) hexahydropyridine-4-carboxylic acid methyl acetate acetate (850 mg, 2.707 mmol). Water was added and the cream precipitate was filtered off and washed with water and dried under high vacuum overnight (when left, the pale yellow solid turned to a brown brown oil). This was dissolved in DCM and loaded onto cerium oxide and eluted with 0-100% ethyl acetate in cyclohexane. Appropriate fractions were combined and the solvent removed to give a clear film which was dried under high vacuum overnight. The four components were separated by chiral preparative HPLC (Method H1 / H2) to give the title compound (239 mg, 16%).

LCMS (Method B): Rt = 1.10 min, MH+ = 556.4.

Intermediate 188: cis-1- (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazol-5-yl-carbonyl) -3- ( 2,2,2-trifluoroacetamido)hexahydropyridine-4-carboxylic acid, single unknown mirror image isomer

Cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] in tetrahydrofuran (THF) (2 mL) and water (1 mL) Addition of LiOH (6.90 mg, 0.288 mmol) to imidazole-5-carbonyl)-3-(2,2,2-trifluoroethylamino)hexahydropyridine-4-carboxylic acid methyl ester (160 mg, 0.288 mmol) The reaction was stirred at rt overnight. The solvent was removed and the residue was taken up in EtOAc EtOAc EtOAc (EtOAc)EtOAc. Appropriate fractions were combined and the solvent was evaporated to give a crystals, which was dried under vacuo to afford white solid (46 mg, 30%).

LCMS (Method B): rt = 0.99 min.

Intermediate 189: cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-3-( 2,2,2-trifluoroacetamido)piperidine-4-carboxamide, single unknown mirror image isomer

To 1,4-dioxane (1 mL) in the cis-1- (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazole Addition of Et ₃ N to -5-carbonyl)-3-(2,2,2-trifluoroethylamino)hexahydropyridine-4-carboxylic acid (46 mg, 0.085 mmol) and HATU (38.8 mg, 0.102 mmol) 0.036 mL, 0.255 mmol) and then 0.5 M ammonia (1 mL, 0.500 mmol) from dioxane and the mixture was stirred overnight. Additional HATU (38.8mg, 0.102mmol), Et 3 N (0.036mL, 0.255mmol) and two of 0.5M ammonia in dioxane (1mL, 0.500mmol) and the reaction was stirred overnight at 70 deg.] C. Additional HATU (38.8mg, 0.102mmol), Et 3 N (0.036mL, 0.255mmol) and two of 0.5M ammonia in dioxane (1mL, 0.500mmol) and the reaction was stirred overnight at 70 deg.] C. The reaction mixture was cooled and the solvent was removed. The crude product was partitioned between ethyl acetate and water (x3). The solvent was removed and the residue was taken up in DCM and applied to EtOAc (EtOAc) Combine the appropriate parts and remove the solvent. The residue was dried under high vacuum for 3 h to give a white solid (8mg, 17%).

LCMS (Method B): Rt = 0.94 min.

Intermediate 190: [(3 R )-1-({2-(1-ethyl-1 H -indol-2-yl)-1-[3-({[(9 H -茀-9-yl)) 1,1-dimethylethyl ester of methyl)oxy]carbonyl}amino)propyl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridyl]carbamic acid

In two equal batches, {(3 R )-1-[(4-{[3-({[(9H-茀-9-ylmethyl)oxy)carbonyl}amino)propyl]] 1,1-nitrophenyl)carbonyl]-3-hexahydropyridyl}aminocarboxylic acid 1,1-dimethylethyl ester (6 g, 9.32 mmol), 1-ethyl-1H-indole 2-formaldehyde (7.844 g, 27.96 mmol) and sodium sulfoxylate (4.868 g, 27.96 mmol) were combined in ethanol (40 mL) and water (20 mL) and heated to 100 ° C using an initial high absorption setting in a Biotage Initiator microwave. Hold for 6h. The reaction mixture was combined and then partitioned between DCM (150 mL) and water (150 mL). The ethanol from the reaction mixture caused the separation of the two layers to be poor, thus evaporating the entire mixture under vacuum - to the point where it was assumed that most of the ethanol was evaporated and only the aqueous layer remained. The aqueous layer was then extracted with DCM (3×100 mL). The organics were combined, dried using a hydrophobic glass and evaporated in vacuo. The sample was loaded in dichloromethane and purified by Biotage SP4 (2 x SNAP 100 g ceria) using a gradient of 50-100% cyclohexane-ethyl acetate. The appropriate fractions were combined and evaporated in vacuo to give the desired product [(3 R )-1-({2-(1-ethyl-1H-indol-2-yl)-1-[ 3-({[(9H-茀-9-ylmethyl)oxy)carbonyl}amino)propyl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinyl]amino 1,1-Dimethylethyl formate (1.83 g, 2.386 mmol, 51.2% yield).

LCMS (Method B): Rt 1.37 min, MH.

Intermediate 191: ( R )-(1-(1-(3-Aminopropyl)-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazole- 3-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

[(3 R )-1-({2-(1-ethyl-1H-indol-2-yl)-1-[3-({[(9H-茀-9-ylmethyl)oxy)oxy) [carbonyl]amino)propyl]-1H-benzimidazol-5-yl}carbonyl)-3-hexahydropyridinyl]1,1-dimethylethylcarbamate (112 mg, 0.146 mmol) and Hexahydropyridine (0.289 mL, 2.92 mmol) was combined in dichloromethane (2 mL) The reaction mixture was evaporated to dryness in vacuo. After ensuring that all of the hexahydropyridine was evaporated, the sample was loaded in dichloromethane and used in a 10-column volume of methanol-dichloromethane 0-5% 2M by Biotage SP4 (SNAP 25 g ceria). The gradient of ammonia was then purified by maintaining 5 column volumes under 5% 2M ammonia in methanol-dichloromethane. The product remained on the column, therefore, using a gradient of 0-20% 2M ammonia in methanol-dichloromethane in 10 column volumes, followed by a 5 column under 20% 2M ammonia in methanol-dichloromethane. Volume to wash the column. The appropriate fractions were combined and evaporated in vacuo to give the desired product ( R )-(1-(1-(3-aminopropyl))-2-(1-ethyl-1H-indole-2 -yl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (79 mg, 0.145 mmol, 99% yield).

LCMS (Method B): Rt 0.83 min, MH+ 545.

Intermediate 192: ((3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl }-3-Hexidopyridinyl)carbamic acid 1,1-dimethylethyl ester.

In a dropwise manner to ((3 R )-1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1-dimethyl Add ethyl hydrogen sulphate to a heterogeneous mixture of ethyl ethyl ester (26.56 g, 70.2 mmol) and 1-ethyl-1 H -indole-2-carbaldehyde (13.51 g, 70.2 mmol) in EtOH (487 mL) A solution of 14.38 g, 70.2 mmol) in water (244 mL). The mixture was flushed with nitrogen and then heated at 90 ° C for 16 h. Additional sodium hydrogen sulfate (8 g, 39.1 mmol) was added in one portion and the reaction mixture was heated at 100 ° C for additional 16 h. The mixture was cooled, then concentrated under reduced pressure and diluted with DCM (1L) and partitioned with water (1L), then filtered over a pad. The organic layer was separated and dried over sodium sulfate. The aqueous phase was further extracted with DCM (1 L×2) and the organic layer was dried with sodium sulfate. The combined organic layers were concentrated under reduced pressure to about half of the original volume, at which time both liquid phases remained apparent. The organic layer was again separated, then the aqueous layer was re-extracted with DCM (2×600 mL). The diatomaceous earth pad was washed with MeOH until the UV active material was no longer dissolved and the laundry was concentrated under reduced pressure. The residue was redissolved in EtOAc (EtOAc)EtOAc. The title compound (14 g) was obtained eluting eluting eluting The material was re-purified by column chromatography eluting with EtOAc (EtOAc)

LCMS (Method B): Rt = 1.15 min, MH+ = 502.3.

The following intermediate system was prepared in a similar manner to intermediate 192:

Intermediate 194: {(3 R )-1-[(2-{1-[(3-Chlorophenyl)methyl]-1 H -indol-2-yl}-1-methyl-1 H - Benzimidazol-5-yl)carbonyl]-3-hexahydropyridyl}aminocarboxylic acid 1,1-dimethylethyl ester.

At rt under nitrogen the vial in 9mL Reacti- ((3 R) -1 - { [4- ( methylamino) -3-nitrophenyl] carbonyl} -3-piperidinyl) amine 1,1-dimethylethyl carbamic acid (150 mg, 0.396 mmol) and 1-[(3-chlorophenyl)methyl]-1H-indole-2-carbaldehyde (107 mg, 0.396 mmol) in ethanol ( To the solution in 4 mL) was added sodium sulfite (162 mg, 0.793 mmol) dissolved in water (2 mL). The reaction mixture was heated to 80 ° C and stirred overnight (18 h). Methanol was added to the reaction mixture, which was then dried over Na ₂ SO ₄ . The reaction mixture was then filtered through gravity through a hydrophobic glass and concentrated under vacuum.

For purification, the reaction mixture was dissolved in 1:1 DMSO / methanol and purified using MDAP (Method A). The product fractions were collected and concentrated under vacuum to give a white solid - {( 3R )-1-[(2-{1-[(3-chlorophenyl)methyl)-1 H -indol-2-yl} 1,1-dimethylethyl ester of 1-methyl- 1H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridyl}carbamic acid (97 mg, 41%).

LCMS (Method B): Rt = 1.30 min, MH ⁺ = 598.5

Intermediate 195: ( R )-(1-(2-(1-(3,4-Dichlorobenzyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

In a manner similar to Intermediate 194 from ((3 R) -1 - { [4- ( methylamino) -3-nitrophenyl] carbonyl} -3-piperidinyl) amino acid 1, Preparation of 1-dimethylethyl ester and 1-[(3,4-dichlorophenyl)methyl]-1H-indole-2-carbaldehyde

LCMS (Method B): Rt = 1.38 min.

Intermediate 196: {(3 R )-1-[(2-{1-[(4-Chlorophenyl)methyl]-1 H -indol-2-yl}-1-methyl-1 H - 1,1-dimethylethyl ester of benzimidazol-5-yl)carbonyl]-3-hexahydropyridyl}carbamic acid

((3 R )-1-{[4-(Methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1- under nitrogen at rt Dimethyl ethyl ester (100 mg, 0.264 mmol) and 1-[(4-chlorophenyl)methyl]-1H-indole-2-carbaldehyde (0.105 mL, 0.396 mmol) in ethanol (2.7 mL) To the solution was added sodium sulfoxylate (162 mg, 0.793 mmol) dissolved in water (1.35 mL). The reaction mixture was heated to 80 ° C and stirred overnight. The reaction was heated for an additional 4 h and then cooled to rt. The reaction mixture was diluted with MeOH (20mL), was added Na ₂ SO ₄ and the resulting suspension was filtered and concentrated in vacuo to yield the crude product as a yellow oil. The crude product was purified using a gradient of 50% ethyl acetate / cyclohexane - > 100% ethyl acetate / cyclohexane over EtOAc (25 g). The appropriate fractions were combined and evaporated under vacuum to yield a product that was still imp. The product was further purified in two batches by MDAP (Method B). The appropriate fractions were combined to give the desired product as a white solid -{(3 R )-1-[(2-{1-[(4-chlorophenyl)methyl]-1H-indol-2-yl}-1 1-Methyl-1H-benzimidazol-5-yl)carbonyl]-3-hexahydropyridyl}carbamic acid 1,1-dimethylethyl ester (61 mg, 0.102 mmol, 38.6% yield).

LCMS (Method B): Rt = 1.31 min, MH ⁺ = 598.5

Other intermediate systems indicated in the table below were prepared in a manner similar to Intermediate 196.

Intermediate 198: [(3 R )-1-({1-methyl-2-[1-(4-pyridylmethyl)-1 H -indol-2-yl]-1 H -benzimidazole -5-yl}carbonyl)-3-hexahydropyridinyl]1,1-dimethylethyl carbamic acid.

((3 R )-1-{[4-(Methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1- under nitrogen at rt Dimethyl ethyl ester (150 mg, 0.396 mmol) and 1-(4-pyridylmethyl)-1H-indole-2-carbaldehyde (103 mg, 0.436 mmol) in ethanol (4 mL) Sodium sulfite (162 mg, 0.793 mmol) in water (2.0 mL). The reaction mixture was heated to 85 ° C and stirred overnight. Additional portion of sodium sulfoxylate (162 mg, 0.793 mmol) in water (2.0 mL) was added and the mixture was warmed to <RTI ID=0.0> The reaction was then heated at 95 ° C for an additional 3 h. An additional amount of sodium sulfoxylate (81 mg, 0.396 mmol) was added and the reaction was heated at 95 ° C overnight. The reaction mixture was diluted with MeOH (20mL), was added Na ₂ SO ₄ and the resulting suspension was filtered and concentrated in vacuo to yield the crude product as a yellow oil. The crude product was purified by a pad of EtOAc (EtOAc) (EtOAc) The appropriate fractions were combined and evaporated under vacuum to yield a product that was still imp. The product was further purified in two batches by MDAP (Method B). The appropriate fractions are combined to give the desired product-[(3 R )-1-({1-methyl-2-[1-(4-pyridylmethyl)-1H-indol-2-yl]- 1H-Benzamidazol-5-yl}carbonyl)-3-hexahydropyridinyl]1,1-dimethylethylcarbamate (107 mg, 0.189 mmol, 47.8% yield).

LCMS (Method B): Rt = 0.91 min, MH ⁺ = 565.5

Intermediate 199: (( R )-1-(2-(1-(( R )-3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-methoxy- 1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

Add ( R )-(1) to a solution of ( R )-1-(3-hydroxy-2-methylpropyl)-1H-indole-2-carbaldehyde (210 mg, 0.967 mmol) in ethanol (10 mL) -(3-Methoxy-4-(methylamino)-5-nitrobenzimidyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (395 mg, 0.967 mmol), after A solution of sodium dithionite (269 mg, 1.547 mmol) in water (5.00 mL) was added. This was heated at 95 ° C for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate and the combined organics were passed through a pad. The organics were concentrated in vacuo to give a crude material. This was dissolved in DCM and purified by EtOAc (EtOAc) eluting eluting Appropriate fractions were combined and concentrated in vacuo to give the title compound as a cream.

LCMS (Method B): Rt 1.13 min.

Intermediate 200: ( R )-(1-(7-Methoxy-1-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole) -2-yl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 199 from ( R )-(1-(3-methoxy-4-(methylamino)-5-nitrobenzylidenyl)hexahydropyridin-3-yl)amine Preparation of tert-butyl formate and 1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-2-carbaldehyde.

LCMS (Method B): Rt 1.16 min, MH+ = 602.3.

Intermediate 201: ( R )-(1-(7-Methoxy-2-(1-(2-methoxyethyl)-1H-indol-2-yl)-1-methyl-1H- Benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 199 from ( R )-(1-(3-methoxy-4-(methylamino)-5-nitrobenzylidenyl)hexahydropyridin-3-yl)amine Preparation of tert-butyl formate and 1-(2-methoxyethyl)-1H-indole-2-carbaldehyde.

LCMS (Method B): Rt 1.15 min.

Intermediate 202: ( R )-(1-(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo [d]imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

In a manner similar to the intermediate 199 from ( R )-(1-(3-methoxy-4-(methylamino)-5-nitrobenzylidenyl)hexahydropyridin-3-yl)amine Preparation of tert-butyl formate and 1-(2-hydroxyethyl)-1H-indole-2-carbaldehyde.

LCMS (Method B): Rt 1.02 min.

Intermediate 203: [(3 R )-1-({1-methyl-2-[1-(3-pyridylmethyl)-1 H -indol-2-yl]-1 H -benzimidazole -5-yl}carbonyl)-3-hexahydropyridinyl]1,1-dimethylethyl carbamic acid

To (( 3R )-1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid 1 in a 5 mL microwave vial at rt. 1-Dimethylethyl ester (148.6 mg, 0.393 mmol) and 1-(3-pyridylmethyl)-1H-indole-2-carbaldehyde (159.2 mg, 0.404 mmol) in ethanol (3.5 mL) To the stirred solution was added sodium sulfoxylate (244.3 mg, 1.193 mmol) dissolved in water (1.5 mL). The reaction mixture was then heated in a microwave at 85 °C for 2 h. The reaction mixture was reheated in the microwave at 90 °C for 1 h. Further sodium sulfoxylate (80 mg, 0.393 mmol) was added to the reaction mixture and the mixture was stirred at 100 ° C for 45 min. Methanol was added to the reaction mixture, which was then dried over Na ₂ SO ₄ . The reaction mixture was then filtered through a pad of water and concentrated under vacuum. The concentrated reaction mixture was purified on a pad of EtOAc (25 g) using 40-100% ethyl acetate /EtOAc. Due to the polarity of the product, the column was subsequently eluted with a gradient of 0-100% (20% methanol in DCM) / DCM. The appropriate fraction from the second purification was collected and concentrated under vacuum to give a yellow/white solid -[( 3R )-1-({1-methyl-2-[1-(3-pyridylmethyl)-) 1 H -Indol-2-yl]-1 H -benzimidazol-5-yl}carbonyl)-3-hexahydropyridinyl]1,1-dimethylethylcarbamate (133 mg, 60% ).

LCMS (Method B): Rt = 0.96 min, MH ⁺ = 565.3

Intermediate 204: ((3 R )-1-{[2-(2,3-Dihydro[1,4]oxazino[2,3,4- hi ]indole-5-yl)-1- 1,1-dimethylethyl ester of methyl-1 H -benzimidazol-5-yl]carbonyl}-3-hexahydropyridyl)carbamic acid

Sodium bisulfite (657 mg, 3.21 mmol) was dissolved in water (3 mL) then added to (( 3R )-1-{[4-(methylamino)-3-nitrophenyl at rt 1,1-dimethylethyl carbonyl}-3-hexahydropyridyl)carbamate (404 mg, 1.07 mmol) and 2,3-dihydro[1,4]oxazine [2,3, 4- hi ]吲哚-5-carbaldehyde (200 mg, 1.07 mmol) in EtOAc (EtOAc) The reaction mixture was heated at 100 ° C for 5 h using microwave then cooled to rt. The reaction mixture was then diluted with EtOAc EtOAc m. The title compound (286 mg, 52%) elute elute

LCMS (Method B): rt = 1.10 min.

Other racemic intermediate systems indicated in the table below were prepared in a manner similar to intermediate 204.

The other intermediate systems in the table below were prepared in a manner similar to intermediate 204:

Intermediate 237: (1-{[2-(1-ethyl-7-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}- 1,1-dimethylethyl 3-hexahydropyridyl)carbamate

1,1-dimethyl by (1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid in a similar manner to the intermediate 204 Preparation of ethyl ester and 1-ethyl-7-methyl-1H-indole-2-carbaldehyde

VT ¹ H NMR (400MHz): (DMSO-d6): δH 7.76 (1H, s), 7.65 (1H, d), 7.52 (1H, m), 7.39 (1H, dd), 7.05-7.01 (2H, m ), 6.97 (1H, s), 6.28 (1H, bd), 4.66 (2H, q), 4.01 (1H, dd), 3.91 (3H, s), 3.82 (1H, m), 3.46 (1H, m) , 3.12 (1H, m), 3.04 (1H, m), 2.78 (3H, s), 1.93 (1H, m), 1.77 (1H, m), 1.53 (2H, m), 1.37 (9H, s), 1.22 (3H, t).

Intermediate 238: (1-{[2-(1-ethyl-5-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}- 1,1-Dimethylethyl 3-hexahydropyridyl)carbamate.

In a similar manner to the intermediate 204, from (1-(4-(methylamino)-3-nitrobenzimidyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester and 1- Preparation of ethyl-5-methyl-1H-indole-2-carbaldehyde.

LCMS (Method B): Rt = 1.22 min, MH ⁺ 516

Intermediate 239: (1 - {[2- (1-ethyl-4-methyl -1H- indol-2-yl) -1-methyl -1H- benzimidazol-5-yl] carbonyl} - 1,1-Dimethylethyl 3-hexahydropyridyl)carbamate.

1,1-dimethyl by (1-{[4-(methylamino)-3-nitrophenyl]carbonyl}-3-hexahydropyridyl)carbamic acid in a similar manner to the intermediate 204 Preparation of ethyl ester and 1-ethyl-4-methyl-1H-indole-2-carbaldehyde

LCMS (Method B): Rt = 1.21 min, MH ⁺ 516

Intermediate 240: (1-(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Pyrrolidin-3-yl)carbamic acid tert-butyl ester

In a similar manner to the intermediate 204, from (1-(3-methoxy-4-(methylamino)-5-nitrobenzylidenyl)pyrrolidin-3-yl)carbamic acid tert-butyl Preparation of base ester and 1-ethyl-1H-indole-2-carbaldehyde.

LCMS (Method B): rt = 1.17 min.

Intermediate 241: cis (+/-) - (1- (2- (1-ethyl -1 H - indol-2-yl) -1-methyl -1 H - benzo [d] imidazole - 3-butyl)-4-methoxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

To cis( +/-)-(1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d] at rt under nitrogen Addition of mineral oil to a stirred solution of imidazole-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester (53 mg, 0.102 mmol) in anhydrous DMF (0.4 mL) 60% NaH (7.17 mg, 0.179 mmol). The mixture was stirred for 10 min while adding methyl iodide (7 μL, 0.112 mmol). The mixture was stirred for 2 h. The reaction mixture was diluted with saturated NH ₄ Cl (aq) (1 mL) and EtOAc (1mL). The organic layer was separated and washed with water (2×1 mL). The organic layer was dried via a hydrophobic glass and the solvent was removed in vacuo. The residue was purified by MDAP (Method B). The appropriate fractions were combined with EtOAcjjjjjjjjjj

LCMS (Method B): Rt: 1.17min, MH + 532.

Intermediate 242: (R) - (1- (2- (1- ethyl--1H- indol-2-yl) -7-hydroxy-1-methyl -1H- benzo [d] imidazole-5 Carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

Add ( R )-(1-(7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene) to a round bottom flask equipped with a stirrer [d] Imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (500 mg, 0.861 mmol), followed by the addition of di-tert-butyl (2', 4', 6'- Triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (30 mg, 0.071 mmol), followed by the addition of bis ( dibenzylideneacetone)dipalladium(0) (35 mg, 0.044 mmol) and KOH (29 mg, 2.58 mmol). The mixture was dissolved in 1,4-dioxane (5 mL) and water (5 mL) was then added and the mixture was rinsed with nitrogen, and then heated at 100 ° C for 16 h. The mixture was concentrated under reduced pressure and then partitioned with water (10 mL) The aqueous layer was re-extracted with EtOAc (2×20 mL). The material was purified by EtOAc EtOAc (EtOAc)

LCMS (Method B): Rt = 1.07 min, MH ⁺ = 518.4

Intermediate 243: ( R )-(1-(7-Cyano-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 -carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

( R )-(1-(7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene) in a Biotage Initiator Microwave Reactor at 150 °C And [d]imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (50 mg, 0.086 mmol) in N,N -dimethylformamide (1 mL) and tetrapalladium (4.98 mg, 4.31 μmol) and zinc dicyano zinc (10.11 mg, 0.086 mmol) were stirred for 4 hr 15 . The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (×2). The organics were combined, washed with brine, dried EtOAc EtOAc EtOAc. Chromatography by Biotage SP4 on a 10 g cerium oxide SNAP column with 0 to 50% ethyl acetate in cyclohexane in 10 column volumes followed by 50% ethyl acetate in cyclohexane at 5 column The oil is purified by dissolution in a volume. The relevant fractions were combined with EtOAc EtOAc m.

LCMS (Method B): Rt = 1.24 min, MH ⁺ = 527.4

Intermediate 244: ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(pyridin-3-yl)-1H-benzo[ d] imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

( R )-(1-(7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[,] in a Biotage Initiator microwave at 100 °C d] Imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (50 mg, 0.086 mmol) in 1,4-dioxane (0.9 mL) and water (0.3 mL) Pyridin-3-yl The acid (11.65 mg, 0.095 mmol), tetrapalladium (9.95 mg, 8.61 μmol) and potassium carbonate (23.81 mg, 0.172 mmol) were stirred for 30 min. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate (x 2), then passed to a water column and concentrated under reduced pressure. The residue was purified by Biotage SP4 chromatography on a 10 g silica gel SNAP column eluting with 0 to 7% methanol in DCM over 15 column volumes. The relevant fractions were combined and concentrated in vacuo to afford title titled

LCMS (Method B): Rt = 1.09min, MH + = 579.5

Intermediate 245: (R) - (1- (7- ylamine acyl-2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazole -5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

( R )-(1-(7-Cyano-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 under nitrogen -carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester (40 mg, 0.076 mmol) and potassium carbonate (20.99 mg, 0.152 mmol) in dimethyl hydrazine (3 mL) and cooled with ice water bath Hydrogen peroxide (0.067 mL, 0.760 mmol, 35% in water) was added dropwise to the stirred suspension. The mixture was brought to rt and stirred at rt under nitrogen for 1 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc.

LCMS (Method B): Rt = 1.05 min, MH ⁺ = 545.4

Intermediate 246: ( R )-(1-(7-ethyl-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 -carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

To ( R )-(1-(7-bromo-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 under nitrogen atmosphere a mixture of -carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (150 mg, 0.258 mmol), Pd(dppf)Cl ₂ (5.28 mg, 6.46 μmol) and cesium carbonate (253 mg, 0.775 mmol) Anhydrous tetrahydrofuran (THF) (4 mL) was added. Triethylborane (1 M solution in THF) (0.8 mL, 0.800 mmol) was added in one portion to a stirred mixture and the mixture was refluxed for 2 h. The reaction was cooled to rt and 50% aqueous acetic acid (4 mL) was added. The solution was refluxed for 1 h and allowed to stand at rt overnight. The solution was extracted with diethyl ether (x 2). The combined organics were washed with brine, dried with EtOAc EtOAc (EtOAc) The residue was taken up in dichloromethane and purified on a pad of EtOAc EtOAc EtOAc (EtOAc) A portion of the large UV peak was combined and evaporated to give a yellow oil (136 mg).

LCMS (Method B): Rt = 1.21min, MH + = 530.3.

Intermediate 247: (2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)(3-hydroxy-5-methyl Hexahydropyridin-1-yl)methanone, a mixture of non-image isomers

2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in N,N-dimethylformamide (DMF) (4 mL) -5-carboxylic acid (200 mg, 0.626 mmol) was added HATU (238 mg, 0.626 mmol) and Et ₃ N (0.175 mL, 1.253 mmol), followed by 5-methylhexahydropyridin-3-ol (72.1 mg, 0.626 mmol) The reaction mixture was stirred overnight. The mixture was partitioned between DCM and saturated citric acid solution (x3). The combined organic layers were washed with citric acid (x 2) and solvent was removed. The residue was dissolved in DCM and applied to EtOAc (EtOAc m. The appropriate portions were combined and the solvent was removed to give a residue which was dried under high vacuum for one week to yield white foam (94 mg, 35%).

LCMS (Method B): Rt = 0.97 min, MH+ = 417.2.

Intermediate 248: 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-5-methyl methanesulfonate Hexahydropyridin-3-yl ester, a mixture of non-image isomers

(2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl) in dichloromethane (10 mL) Add 3-methylsulfonium chloride (0.021 mL, 0.265 mmol) and Et ₃ N (0.037 mL, 0.265 mmol) and The reaction was stirred overnight under nitrogen. Additional Et ₃ N (0.037 mL, 0.265 mmol) and methanesulfonium chloride (0.021 mL, 0.265 mmol) were added and reacted for 3 h. The residue was partitioned between DCM and water (x3). The combined organic layers were washed with water and the solvent was removed. The residue was dried under EtOAc (EtOAc) EtOAc (EtOAc)

LCMS (Method B): rt = 1.11 min.

Intermediate 249: (3-azido-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene And [d]imidazol-5-yl)methanone, a mixture of non-image isomers

1-(2-(1-Ethyl-1H-indol-2-yl)-1-methyl-1H-methanesulfonate in N-methyl-2-pyrrolidone (NMP) (5 mL) Addition of sodium azide (28.7 mg, 0.442 mmol) to benzo[d]imidazol-5-carbonyl)-5-methylhexahydropyridin-3-yl ester (109 mg, 0.221 mmol) and the reaction at 90 ° C Stir under nitrogen overnight. Additional NaN ₃ (20 mg) was added and allowed to react overnight. The solution was partitioned between ethyl acetate and water (x3) and the combined organic layers were washed with water and solvent. The residue was dissolved in DCM and applied to EtOAc (EtOAc m. The appropriate fractions were combined and the solvent was evaporated to afford white crystals.

LCMS (Method B): rt = 1.19 min.

Intermediate 250: ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-thioformamidine Carbonothioyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

To ((3 R )-1-{[2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexa Lawesson's reagent (17.42 mg, 0.043 mmol) was continuously added to a solution of 1,1-dimethylethyl (hydrogen pyridyl)aminocarbamate (36 mg, 0.072 mmol). The reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to rt, concentrated in vacuo and taken directly to next.

LCMS (Method B): rt = 1.24 min.

Intermediates 251 and 252: ((3 S ,4 R )-1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d] Imidazole-5-carbonyl)-4-fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester and ((3 R ,4 S )-1-(2-(1-ethyl-1H-indole)哚-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)-4-fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester single unknown mirror isomerism Object

To ( cis -(+/-)-3-amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-yl Add a di-t-butyl dicarbonate (48.8 mg, 0.223) to a stirred solution of yl- 1H -benzo[d]imidazol-5-yl)methanone (85.2 mg, 0.203 mmol) in DCM (5 mL) Methyl) followed by DIPEA (0.043 mL, 0.244 mmol). The resulting suspension was stirred at rt for 3 h then allowed to stand for 16 h (over night). The crude product was purified by silica gel chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) The appropriate fractions were combined and evaporated <RTI ID=0.0> The mixture was subjected to chiral separation (Method N). Isomer 1 (45 mg) and isomer 2 (36 mg) were isolated separately.

Isomer 1: LCMS (Method B): Rt = 1.16 min, MH+ = 520.3.

Isomer 2: LCMS (Method B): Rt = 1.17 min, MH+ = 520.3.

Intermediate 253: ( R )-(1-(2-(1-(cyclopropylmethyl)-6-methoxy-1 H -indol-2-yl)-1-methyl-1 H - Benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

1-(Cyclopropylmethyl)-6-methoxy-1 H -indole-2-carboxylic acid (169 mg, 0.517 mmol) was dissolved in DMF (2 mL) and HATU (216 mg, 0.568) Methyl) and DIPEA (0.271 mL, 1.550 mmol). The reaction was stirred at rt for 30 min, then ( R )-(1-(3-amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl)carbamic acid was added. Tributyl ester (180 mg, 0.517 mmol). The reaction was stirred at 45 ° C for 5.5 h. The reaction mixture was cooled and quenched with EtOAc (EtOAc) The mixture (3 × 10mL) and extracted with EtOAc and the combined organics were washed with NaHCO ₃ followed by brine, dried and concentrated to yield (324 mg of) the crude product was a deep blue. The crude product was purified by silica gel chromatography on EtOAc EtOAc (EtOAc) eluting The appropriate fractions were combined and evaporated <RTI ID=0.0> This was dissolved in toluene (10 mL) and EtOAc (EtOAc &lt Another 30 μL of acetic acid was added and the mixture was refluxed for an additional 1 hour. The reaction mixture was cooled and the EtOAc was evaporated. The crude product was purified by silica gel chromatography eluting with EtOAc EtOAc EtOAc (EtOAc) Appropriate fractions were combined and the volatiles were removed under reduced pressure to give an orange oil (R) - (1- (2- (1- ( cyclopropylmethyl) -1H- indole-6-methoxy - 2-Butyl-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (147 mg, 0.264 mmol, 51.0% yield) .

LCMS (Method B): rt = 1.16 min.

Intermediate 254: 1-(Cyclopropylmethyl)-6-methoxy-1 H -indole-2-carboxylic acid

6-Methoxy-1 H -indole-2-carboxylic acid methyl ester (243 mg, 1.101 mmol) was dissolved in DMF (4 mL), and sodium hydride (44.0 mg, 1.101 mmol, in mineral oil) 60% dispersion). The reaction was stirred for 5 min and then (bromomethyl)cyclopropane (0.107 mL, 1.101 mmol). After 40 min, LCMS showed 53% starting material and 28% of desired product methyl ester. The reaction was stirred for one week. LCMS showed an increase in the methyl ester of the desired product. Additional (bromomethyl)cyclopropane (0.5 mL, 5.16 mmol) was added and the mixture was stirred further 40 min. LCMS showed an increase in the methyl ester (39%) of the product. The reaction was stirred for a further 3 h. LCMS showed little change. An aliquot of sodium hydride was added and the reaction was stirred for 1 h. A further aliquot of bromomethylcyclopropane was added. Additional sodium hydride (44.0 mg, 1.101 mmol) was added and the mixture was stirred overnight. A further aliquot of bromomethylcyclopropane (0.5 mL, 5.16 mmol) was added to the reaction mixture. The solution was stirred for an additional 2.5 h. Additional sodium hydride (44.0 mg, 1.101 mmol) was added <RTI ID=0.0> A further aliquot of bromomethylcyclopropane (0.5 mL, 5.16 mmol) was added to the reaction mixture and the solution was stirred 1 h. LCMS showed 13% starting material, 33% of desired product methyl ester and 39% of desired product. A further aliquot of bromomethylcyclopropane (0.5 mL, 5.16 mmol) was added to the reaction mixture and the solution was stirred for 4 h. Sodium hydride (44 mg, 1.101 mmol) was added to the reaction and the solution was stirred 30 min. LCMS showed 64% conversion to the desired product. NaOH (1 mL, 2 mmol, 2 M) was carefully added to the mixture and the mixture was stirred for 1.5 h. A further aliquot of NaOH (1 mL, 2 mmol) was added to the reaction and the solution was stirred for additional 30 min. LCMS showed 78% conversion to the desired product. The aqueous layer was acidified with NH ₄ Cl (saturated) and extracted with 3 × EtOAc. The combined organic layers were taken to abr. EtOAc (EtOAc). This product was crude for subsequent reaction.

LCMS (Method B): Rt = 1.01 min.

Intermediate 255: 6-Methoxy -1 H - indole-2-carboxylic acid methyl ester

6-Methoxy-1 H -indole-2-carboxylic acid (1 g, 5.23 mmol, available from, for example, Amfinecom Inc.) was dissolved in methanol (16 mL), and HCl (12.39 M, 1.689 mL, 20.92 mmol). The reaction was stirred at 65 ° C under nitrogen for 3 h. The reaction was stirred at 65 &lt;0&gt;C under nitrogen overnight and LCMS showed 43% conversion to the desired product. The reaction was stirred at 65 ° C for a further 4.5 h under nitrogen. The solution was then allowed to cool and reached pH 14 using NaOH (2M). The desired product was filtered to give the desired product ( 328mg).

LCMS (Method B): Rt = 0.92 min, MH+ = 4421.

Intermediate 256: 1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-carboxamido)-3 -azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester

Triethylamine (0.191 mL, 1.399 mmol) and 1-amino-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (99 mg, 0.466 mmol) in DMF (5 mL) 2-(1-Ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-carboxylic acid (149 mg, 0.466 mmol) and HATU were added to the mixture. (213 mg, 0.560 mmol). The reaction was then stirred at rt under nitrogen for 4 h. The reaction mixture was partitioned between DCM and water (×3). The solvent was then evaporated to leave a brown oil and LCMS showed two major components left in the reaction mixture with a retention time of 1.22 and 1.26. Separation was successfully carried out using a 25 g ruthenium dioxide column using 0-50% ethyl acetate in cyclohexane. The appropriate portion of the product is recombined to produce a more pure product. After drying, a white solid 1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-carboxamide -3-Azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (144 mg, 0.255 mmol, 54.7%) which was used in the next chemistry without further purification.

LCMS (Method B): rt = 1.22 min.

Intermediate 257: (1- (2- (1-Benzyl--1 H - indol-2-yl) -1-methyl -1 H - benzo [d] imidazol-5-yl-carbonyl) piperidine - 3-yl) butyl carbamate

In the similar manner to Intermediate 145 from 1-methyl-2- [1- (phenylmethyl) lH-indol-2-yl] -1 H - benzimidazole-5-carboxylic acid and pipecolic Preparation of 3-butylaminocarbamic acid tert-butyl ester.

¹ H NMR (400 MHz, DMSO-d ₆ , 393 K) δ </ RTI></RTI></RTI> 7.76 - 7.69 (m, 2 H) 7.59 (d, J = 8.3 Hz, 1 H) 7.52 (d, J = 8.3 Hz, 1 H) 7.36 ( Dd, J = 8.3, 1.3 Hz, 1 H) 7.26 (t, J = 7.6 Hz, 1 H) 7.19 - 7.08 (m, 5 H) 7.00 - 6.93 (m, 2 H) 6.17 (d, J = 6.8 Hz) , 1 H) 5.84 (s, 2 H) 3.99 (dd, J =12.7, 3.9 Hz, 1 H) 3.87-3.74 (m, 4 H) 3.52-3.39 (m, 1 H) 3.12 (ddd, J =13.2) , 9.9, 3.1 Hz, 1 H) 3.04 (dd, J =12.7, 8.9 Hz, 1 H) 1.97-1.89 (m, 1 H) 1.79-1.71 (m, 1 H) 1.59-1.46 (m, 2 H) 1.35 (s, 9 H).

Intermediate 258: (+/-)-( trans )-4-fluoro-3-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester

Triethylamine hydrofluoride (2.502 mL, 15.35 mmol) was delivered from the clamp bottle to a PTFE tube where the previous transfer of 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid benzyl Base ester (3.58 g, 15.35 mmol). The resulting mixture was heated at 100 °C. After 4 h, the mixture was cooled. The mixture (clear light yellow oil) was reheated at 100 ° C for another 90 min, then allowed to reach rt and aged for 14 h. By carefully added dropwise with stirring a saturated aqueous solution of NaHCO ₃ (25mL) The mixture was quenched (clear pale yellow oil), then extracted with DCM (50mL × 3). The organics were combined and washed with brine, dried over EtOAc EtOAc EtOAc. The crude product was purified by chromatography on a pad of EtOAc (EtOAc) elute The appropriate fractions were combined and crystalljjjjjjjjjjjj

LCMS (Method B): Rt = 0.85 min, MH+ = 254

Intermediate 259: (+/-)-( trans )-4-fluoro-3-((methylsulfonyl)oxy)hexahydropyridine-1-carboxylic acid benzyl ester

(+/-)-( trans )-4-fluoro-3-hydroxyhexahydropyridine-1-carboxylic acid benzyl ester (2.78 g, 10.98 mmol) and triethylamine (3.82 mL, 27.4 mmol) under nitrogen A solution of methanesulfonic anhydride (3.82 g, 21.95 mmol) in anhydrous DCM (20 mL) was added dropwise in EtOAc EtOAc. At the end of the addition, the mixture was allowed to reach rt and stirred for 1 h. The reaction mixture was treated with a saturated solution of NaHCO ₃ (aq) (50 mL) and brine (50mL). The organic layer was dried over a pad of EtOAc (EtOAc)EtOAc. (4.51g, 124%)

LCMS (Method B): Rt = 0.97 min, MH+ = 332

Intermediate 260: (+/-)-(cis)-3-azido-4-fluorohexahydropyridine-1-carboxylic acid benzyl ester

Benzyl (+/-)-(cis)-4-fluoro-3-((methylsulfonyl)oxy)hexahydropyridine-1-carboxylate (2.9 g, 8.75 mmol) under nitrogen Sodium azide (2.086 g, 32.1 mmol) was added to a stirred solution of anhydrous DMF (11 mL). The resulting mixture was heated at 90 ° C and then aged for one week (57 hours). LCMS showed the starting material. The mixture was stirred at EtOAc (EtOAc) (EtOAc) The combined organics were washed with brine (3 × 60mL), dried over Na ₂ SO ₄ and the volatiles were removed under reduced pressure to afford 1.9g of crude product. The crude product was purified by chromatography on EtOAc EtOAc EtOAc (EtOAc) The title compound (888 mg, 3.19 mmol, 36.5% yield).

LCMS (Method B): Rt = 1.07 min, MH+ = 279

Intermediate 261: (+/-)-(cis)-3-amino-4-fluorohexahydropyridine-1-carboxylic acid benzyl ester

(+/-)-(cis)-3-azido-4-fluorohexahydropyridine-1-carboxylic acid benzyl ester (888 mg, 3.19 mmol) in tetrahydrofuran (THF) (25 mL) and water Triphenylphosphine (1256 mg, 4.79 mmol) was added to the stirred solution in (0.625 mL). The resulting mixture was heated at 35 &lt;0&gt;C for 2 h, then heated at 50 &lt;0&gt;C for additional 2 h then aging for 16 h at rt. The mixture was loaded onto the SCX column pre-equilibrated 10g, after the in MeOH 2M NH ₃ (3CV) eluted with MeOH (3CV),. The basic portion was combined and the volatiles were removed under reduced pressure to give a crude mixture of desired product and triphenylphosphine oxide. The mixture was diluted with a 10% KH ₂ PO ₄ solution and the pH was measured, and solid KH ₂ PO _{4 was added} to reach pH = 4 (up to the solubility limit). When the solution pH is maintained at 5, and the solution was neutralized with solid NaHCO ₃ and again (effervescence!) And 10% citric acid in water of in an attempt was acidified to pH = 4. Unsuccessful and pH was maintained at pH=5. The resulting solution was extracted with EtOAc and analysis showed that the desired product was not isolated from triphenylphosphine oxide. At the second extraction, methanol was inadvertently used in place of EtOAc. The aqueous + methanol solution was reduced in vacuo and combined with the organic layer and subsequently reduced in vacuo. Using 1.0M HCl and the resulting mixture was acidified to 2 and extracted with EtOAc (× 3) pH =, followed by powdered NaHCO ₃ and (caution effervescence!). The (× 3) and the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried over Na ₂ SO ₄ and the volatiles were removed under reduced pressure to afford the title compound as an off-white solid (523mg, 2.074mmol, 65.0% yield).

LCMS (Method B): Rt = 0.53 min, MH+ = 253.1

Intermediate 262: (+/-)-(cis)-3-((t-butoxycarbonyl)amino)-4-fluorohexahydropyridine-1-carboxylic acid benzyl ester

Benzyl (+/-)-(cis)-3-amino-4-fluorohexahydropyridine-1-carboxylate (523 mg, 2.074 mmol) in chloroform (6 mL) and triethylamine (0.347) To the stirred solution of mL, 2.489 mmol) was added di-tert-butyl dicarbonate (498 mg, 2.282 mmol). The resulting mixture was stirred for 3 hours. The mixture was then diluted with the addition of DCM and extracted with NaHCO _{3 (3} × 60mL), dried and the volatiles were removed under reduced pressure on a hydrophobic frit to give 0.87g crude product. The crude product was purified by silica gel chromatography (25 g EtOAc EtOAc) eluting with EtOAc EtOAc The title compound (700 mg, 1.86 mmol, 96%) was obtained.

LCMS (Method B): Rt = 1.14 min, MH+ = 353

Intermediate 263: (+/-)-((cis)-4-fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester

Hydrogenation (+/-)-(cis)-3-((t-butoxycarbonyl)amine group using a flow device (H-cube, set, flow rate 1 mL/min, perhydrogen, 1 atm, ambient temperature) Benzyl-4-fluorohexahydropyridine-1-carboxylate (700 mg, 1.986 mmol) in methanol (40 mL). After 10 min, TLC and NMR of the sample showed complete conversion. The volatiles were removed under reduced br

¹ H NMR (400 MHz, 393 K, DMSO-d ₆ ) δ ppm 5.90 (br.s., 1 H) 4.76 (ddt, J = 50.1, 6.0, 2.9, 2.9 Hz, 1 H) 3.54-3.68 (m, 1 H) 2.58-2.79 (m, 4 H) 1.60-1.89 (m, 2 H) 1.42 (s, 9 H)

Example 1a: (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}- 3-hexahydropyridinium

To ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridine-3 To a solution of <RTI ID=0.0># </RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The reaction mixture was concentrated in vacuo to give a yellow oil. This was dissolved in methanol and loaded onto an SCX column (10 g). This was dissolved in methanol (3 column volumes) and the product was eluted to the free base using 2M ammonia in methanol. The filtrate from the ammonia fraction was concentrated in vacuo to give a yellow solid -( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl) 1-methyl-1H-benzo[d]imidazol-5-yl)methanone (652 mg, 1.624 mmol, 93% yield).

LCMS (formic acid): Rt = 0.79 mins, MH ⁺ = 402.2

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm: 7.78-7.69 (m, 3H), 7.63 (d, 1H), 7.36 (d, 1H), 7.31 (dd, 1H), 7.15 (dd, 1H) , 7.09 (m, 1H), 4.61 (q, 2H), 4.35-4.01 (m, 1H), 3.98 (s, 3H), 3.75-3.35 (m, 1H), 3.02-2.87 (m, 1H), 2.79 - 2.58 (m, 2H), 1.93-1.83 (m, 1H), 1.79-1.54 (m, 2H), 1.53-1.42 (m, 1H), 1.28 (t, 3H).

Example 1b: (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl]carbonyl}- 3-hexahydropyridinium, hydrochloride

To a ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzoate in a 20 mL vial Add HCl (1.0M in Et ₂ O in) (0.533mL, 0.533mmol) (5mL ) in a solution of [d] imidazol-5-yl) methanone (214mg, 0.533mmol) in dichloromethane (DCM) and The reaction was stirred at rt for 15 min. The initial precipitation occurred when HCl was added, but disappeared upon agitation. The solvent was removed in vacuo and the sample dried under a positive pressure of nitrogen to give a pale yellow solid - (R) - (3- amino-hexahydro-1-yl) (2- (1-B Base-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (231 mg, 0.527 mmol, 99% yield).

LCMS (formic acid): Rt = 0.78 mins, MH ⁺ = 402.2

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm: 8.28 (br.s, 3H), 7.88 (s, 1H), 7.84 (d, 1H), 7.73 (d, 1H), 7.66 (d, 1H) , 7.49(d,1H), 7.34(dd,1H), 7.20(s,1H), 7.20-7.15(m,1H),4.58(q,2H),4.32-4.05(m,1H),4.02(s , 3H), 3.75-3.35 (m, 1H), 3.35-3.03 (m, 3H), 2.12-2.01 (m, 1H), 1.84-1.73 (m, 1H), 1.73-1.61 (m, 1H), 1.61 - 1.47 (m, 1H), 1.27 (t, 3H).

Other examples indicated in the table below were prepared analogously to Example 1a. In some cases, further purification by Mass Directed Autoprep is required using standard procedures.

The examples indicated in the table below were prepared analogously to Example 1a. In some cases, by quality The amount of orientation was automatically prepared for further purification.

Example 42: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzene And [d]imidazol-5-yl)methanone

In a manner similar to that of Example 1a, from ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1,6-dimethyl-1H-benzo[d]imidazole Preparation of -5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt 0.83 min, MH+ = 416.

Example 11b: (3 R )-1-({1-methyl-2-[1-(2,2,2-trifluoroethyl)-1 H -indol-2-yl]-1 H -benzene Imidazolyl-5-yl}carbonyl)-3-hexahydropyridinamine, hydrochloride

In a similar manner to Example 1b from ( R )-(3-aminohexahydropyridin-1-yl)(1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H -Indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone.

LCMS (Method A): Rt = 1.01 min, MH ⁺ = 456.2

Example 33b: ((R) -3- amino-hexahydro-1-yl) (2- (1 - (( R) -3- hydroxy-2-methylpropyl) lH-indole-2 -7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a manner analogous to Example 1b from (( R )-3-aminohexahydropyridin-1-yl)(2-(1-((R)-3-hydroxy-2-methylpropyl)-1H-) Preparation of indole-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone.

LCMS (Method C): Rt 0.76 min.

Example 43: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

In a manner analogous to Example 1b from ( R )-(1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1-methyl- Preparation of 1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt = 0.89 min, MH ⁺ = 458.3

Example 44: ( R )-(3-Aminohexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)- 1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

In a manner similar to that of Example 1b from ( R )-(1-(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indole- Preparation of 2-butyl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.89 min, MH ⁺ = 458.3

Example 45: ( 3S )-1-({1-Methyl-2-[1-(phenylmethyl)-1 H -indol-2-yl]-1 H -benzimidazol-5-yl }carbonyl)-3-hexahydropyridinamine.

From [( 3S )-1-({1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazole in a similar manner to Example 1a Preparation of 1,1-dimethylethyl ester of -5-yl}carbonyl)-3-hexahydropyridyl]carbamic acid.

LCMS (Method B): Rt = 0.88 min, MH ⁺ = 464.4.

Example 46: ( S )-(3-Aminohexahydropyridin-1-yl)(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d Imidazole-5-yl)methanone.

From ((3 S )-1-{[1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzimidazol-5-yl) in a similar manner to Example 1a Preparation of 1,1-dimethylethyl carbonyl}-3-hexahydropyridyl)carbamate

LCMS (Method B): Rt = 0.69 min, MH+ = 388.2

Example 47: (1 R , 5 S )-3-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl] Carbonyl}-3-azabicyclo[3.1.0]hex-1-amine.

In a manner similar to that of Example 1a, ((1 R , 5 S )-3-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Preparation of imidazole-5-carbonyl)-3-azabicyclo[3.1.0]hex-1-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.77 min, MH ⁺ = 400.1

Example 48: ( R )-(1-(2-Aminoethyl)-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl) (3-aminohexahydropyridin-1-yl)methanone

In a manner similar to that of Example 1a, ((3 R )-1-{[1-[2-({[(1,1-dimethylethyl)oxy)carbonyl)amino)ethyl]-2) 1-(1-ethyl-1H-indol-2-yl)-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1-dimethylethyl ester preparation

LCMS (Method A): Rt = 0.80 min, MH ⁺ = 431.24

Example 49: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethyl) -1H-benzo[d]imidazol-5-yl)methanone

In a manner similar to that of Example 1a, from ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(trifluoromethyl)-1H- Preparation of benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt = 0.92 min, MH ⁺ = 470.3

Example 50: (+/-)- cis- (3-Amino-4-ethoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone

In a manner similar to that of Example 1a from (+/-)-cis (4-ethoxy-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H) -Preparation of benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt = 0.86min, MH + = 446.3.

Example 51: (+/-)-(( trans) -3-amino-4-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone

In a manner similar to that of Example 1a from (+/-)-((cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo [d]imidazole-5-carbonyl)-4-methoxyhexahydropyridin-3-yl)carbamic acid Preparation of third butyl ester

LCMS (Method A): Rt = 0.97 min, MH ⁺ = 432.22

Example 52: cis- (3-Amino-2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone hydrochloride, a single unknown mirror image isomer with known relative stereochemistry

From the cis- (1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl group in a similar manner to Example 1a Preparation of tert-butyl 2-methylhexahydropyridin-3-yl)carbamate.

LCMS (Method B): Rt = 0.80 min, MH+ = 416.2.

Example 53: cis- (5-Amino-2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone hydrochloride, a single unknown mirror image isomer with known relative stereochemistry

From ((cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 in a similar manner to Example 1a Preparation of -carbonyl)-6-methylhexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt = 0.81 min, MH+ = 416.1.

Example 54: cis- (5-Amino-2-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone hydrochloride, a single unknown mirror image isomer with known relative stereochemistry

From ((cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 in a similar manner to Example 1a Preparation of -carbonyl)-6-methylhexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.81 min, MH+ = 416.1.

Example 55: N-(azepan-3-yl)-2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-carbamide hydrochloride

From 3-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5 in a similar manner to Example 1a -Methylamino)azetidane-1-carboxylic acid tert-butyl ester preparation

LCMS (Method B): Rt = 0.84 min, MH+ = 442.3.

Example 56: (3-Aminopyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[ d]imidazol-5-yl)methanone hydrochloride

In a manner similar to that of Example 1a, from (1-(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole- Preparation of tert-butyl 5-carbonyl)pyrrolidin-3-yl)carbamate.

LCMS (Method B): Rt = 0.81 min.

Example 57: (3-Aminopyrrolidin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5- Ketone

In a manner similar to that of Example 1a, from [1-({1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl} Preparation of 1,1-dimethylethyl carbonyl)-3-pyrrolidinyl]carbamic acid. LCMS (Method B): Rt = 0.86 min, MH+ = 450.4

Example 58a: ((3 S ,4 R )-3-Amino-4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2, 2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone

In a manner similar to that of Example 1a, (4-hydroxy-1-(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl)-1H-indole- Preparation of 2-butyl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.88 min, MH ⁺ = 502.3

Example 58b: ((3 S ,4 R )-3-Amino-4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2, 2-Trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

The manner analogous to Example 1b from ((3 S, 4 R) -3- amino-4-hydroxy-piperidine-1-yl) (7-methoxy-1-methyl-2- (1 Preparation of (2,2,2-trifluoroethyl)-1 H -indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone.

LCMS (Method B): Rt = 0.86 min, MH ⁺ = 5021.

Example 59: ((3 R ,4 S )-3-Amino-4-hydroxyhexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-(2,2, 2-trifluoroethyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone

In a manner similar to that of Example 1a ((3 R , 4 S )-4-hydroxy-1-(7-methoxy-1-methyl-2-(1-(2,2,2-trifluoroethyl) yl) -1 H - indol-2-yl) lH-benzo [d] imidazol-5-carbonyl) hexahydro-pyridin-3-yl) carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.82 min, MH ⁺ = 502.3.

Example 20b: (3 R )-1-[(1-Methyl-2-{1-[(1-methyl-1 H -pyrazol-4-yl)methyl]-1 H -吲哚-2 -yl}-1 H -benzimidazol-5-yl)carbonyl]-3-hexahydropyridylamine hydrochloride

To ( R )-(1-(1-methyl-2-(1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-indol-2-yl)-1H Adding TFA to a solution of benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (144 mg, 0.254 mmol) in dichloromethane (EtOAc) (0.6 ml, 7.79 mmol) and stirred at rt for 40 min. The reaction mixture was concentrated in vacuo and then taken up in MeOH and loaded onto 5g. The column was eluted with MeOH (3 column volumes) and product was eluted to the free base using 2M ammonia (4 column volume) in MeOH. The product fractions were collected and concentrated under vacuum to give a yellow solid. The product was dissolved in a minimum volume of DCM and hydrochloric acid (1M in diethyl ether) (0.178 <RTIgt; The solvent was removed under nitrogen and then dried under vacuum to give ( 3R )-1-[(1-methyl-2-{1-[(1-methyl-1 H -pyrazol-4-yl) Methyl]-1 H -indol-2-yl}-1 H -benzimidazol-5-yl)carbonyl]-3-piperidine hydrochloride (64 mg, 50%).

LCMS (Method A): Rt = 0.86 min, MH ⁺ = 468.2

Example 6b: (3 R )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-7-(methyloxy)-1 H -benzo Imidazol-5-yl]carbonyl}-3-hexahydropyridinium hydrochloride

Similar to Example 20b from ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole Preparation of -5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt 0.80 min, MH+ = 432.3

Example 60: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-5-fluoro-1H-indol-2-yl)-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone, hydrochloride

Real similar ^- from Example 20b (R) - (1- (2- (1- ethyl-5-fluoro -1H- indol-2-yl) -1-methyl -1H- benzo [d] imidazole Preparation of -5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt 0.79 min, MH+ = 420.1

Example 61: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(pyridine-3 -yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

In a similar manner to Example 20b, from (R)-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(pyridin-3-yl)-1H Preparation of benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.84 min, MH ⁺ = 479.3

Example 62: ( R )-5-(3-Aminohexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo [d]imidazole-7-formamide, hydrochloride.

In a manner analogous to Example 20b from ( R )-(1-(7-aminocarbamido-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo) Preparation of [d]imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.72 min, MH ⁺ = 445.2

Example 63: ( R )-(3-Aminohexahydropyridin-1-yl)(7-(dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1 -Methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

In a manner analogous to Example 20b from ( R )-(1-(7-(dimethylamino)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H -Preparation of benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method A): Rt = 1.09 min, MH+ = 445.4.

Example 64: 2-(1-Ethyl-1H-indol-2-yl)-1-methyl-N-(1,4-oxazepan-6-yl)-1H-benzo[d Imidazole-5-carbamide hydrochloride

From 6-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxamido) in a similar manner to Example 20b Preparation of -1,4-oxazepan-4-carboxylate tert-butyl ester.

LCMS (Method B): Rt = 0.779 min.

Example 65: ((3 S ,4 R )-3-Amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone hydrochloride

From ((3 S ,4 R )-1-(2-(1-(cyclopropylmethyl)-1 H -indol-2-yl)-1-methyl-1) in a similar manner to Example 20b Preparation of tert-butyl H -benzo[d]imidazol-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamate.

LCMS (Method B): Rt = 0.83 min, MH ⁺ = 444.3

Example 66: ((3 S ,4 R )-3-Amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-1H-indol-2-yl) )-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a similar manner to Example 20b from (( 3S , 4R )-1-(2-(1-(cyclopropylmethyl)-1H-indol-2-yl)-7-methoxy-1 Preparation of -methyl-1H-benzo[d]imidazol-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.85 min, MH+ = 474.2

Example 67: ((3 S ,4 R )-3-Amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-- Oxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

From ((3 S ,4 R )-1-(2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H in a similar manner to Example 20b Preparation of benzo[d]imidazol-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.82 min, MH+ = 448.3

Example 68: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-7-(methylamine -1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a similar manner to Example 20b from ( R )-(5-(3-((t-butoxycarbonyl)amino) hexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indole Preparation of tert-butyl ester of ind-2-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)(methyl)aminocarbamate.

LCMS (Method B): Rt = 0.71 min, MH+ = 431.2

Example 69: ( R )-(3-Aminohexahydropyridin-1-yl)(7-methoxy-2-(1-(3-methoxypropyl)-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a manner similar to that of Example 20b from ( R )-(1-(7-methoxy-2-(1-(3-methoxypropyl)-1H-indol-2-yl)-1-yl Preparation of tert-butyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamate.

LCMS (Method A): rt = 1.03 min.

Example 70: ( R )-(3-Aminohexahydropyridin-1-yl)(7-methoxy-1-methyl-2-(1-((tetrahydro-2H-pyran-4-yl) )methyl)-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a similar manner to Example 20b from (R)-(1-(7-methoxy-1-methyl-2-(1-((tetrahydro-2H-pyran-4-yl)methyl))) Preparation of 1H-indol-2-yl)-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.88 min, MH+ = 502.4.

Example 71: ( R )-(3-Aminohexahydropyridin-1-yl)(7-methoxy-2-(1-(2-methoxyethyl)-1H-inden-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a manner similar to that of Example 20b, from ( R )-(1-(7-methoxy-2-(1-(2-methoxyethyl)-1H-indol-2-yl)-1-yl) Preparation of tert-butyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamate.

LCMS (Method C): Rt = 0.73 min.

Example 72: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-7-methoxy- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a manner analogous to Example 20b from ( R )-(1-(2-(1-(2-hydroxyethyl)-1H-indol-2-yl)-7-methoxy-1-methyl- Preparation of 1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.76 min, MH+ = 448.4.

Example 73: (( R )-3-Aminohexahydropyridin-1-yl)(2-(1-(( S )-3-hydroxy-2-methylpropyl)-1H-indole-2- -7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

In a similar manner to Example 20b from (( R )-1-(2-(1-(( S )-3-hydroxy-2-methylpropyl)-1H-indol-2-yl)-7-) Preparation of methoxy-1-methyl-1H-benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.84 min, MH+ = 476.3.

Example 74: ( R )-2-(2-(5-(3-Aminohexahydropyridine-1-carbonyl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-2 -yl)-1H-indol-1-yl)acetonitrile, hydrochloride

In a manner analogous to Example 20b from ( R )-(1-(2-(1-(cyanomethyl)-1H-indol-2-yl)-7-methoxy-1-methyl-1H Preparation of benzo[d]imidazol-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.81 min.

Example 75: (R) - (3- amino-hexahydro-1-yl) (7-ethyl-2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H -benzo[d]imidazol-5-yl)methanone, hydrochloride

In a similar manner to Example 20b from ( R )-(1-(7-ethyl-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Preparation of imidazole-5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.85 min, MH+ = 430.3.

Example 76: N -(Azepan-3-yl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5- Formamide

To 3-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carboxamido)azepane-1 To a stirred solution of tributyl carboxylic acid (103 mg, 0.20 mmol) in EtOAc (EtOAc) After stirring at rt for 17 h, the reaction mixture was concentrated in a Radleys purge apparatus under nitrogen flow to yield a yellow oil. The residue was loaded into a 5 g SCX column in MeOH, which was pre-conditioned with MeOH. The column was washed with MeOH (4 CV) and product was eluted using methanolic ammonia (2M) (4 CV). The appropriate fractions were combined and the solvent was removed under reduced pressure to give crude material. The residue was dissolved in MeOH / EtOAc (1:1) (1 mL). The appropriate portions are combined and the solvent is removed under reduced pressure to give the desired product N-(azepan-3-yl)-2-(1-ethyl-1H-indol-2-yl) as a white solid. 1-Methyl-1H-benzo[d]imidazole-5-carboxamide (59 mg, 0.14 mmol, 71.1% yield).

LCMS (Method B): Rt = 0.84 min, MH ⁺ = 416.2

Example 77: (S) - N -(azepan-3-yl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-formamide

From N- (azepan-3-yl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-formamidine The amine was prepared by chiral purification chromatography (Method I). The combined from the appropriate portion of the first eluted isomer and concentrated under reduced pressure to give a clear oil (S) - N - (azepan-3-yl) -2- (1-ethyl -1H -Indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-carboxamide (9 mg, 0.022 mmol).

LCMS (Method B): Rt = 0.84 min, MH ⁺ = 416.2

Example 78: ( R )-N-(1-(2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Hydropyridin-3-yl)-2-chloroacetamidine

To contain (3 R )-1-({1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl}carbonyl) To a flask of -3-hexahydropyridinamine (21 mg, 0.045 mmol) and N,N-dimethylformamide (DMF) (1 mL) was added ethyl 2-chloroethyl acetimidate (10.74 mg, 0.068) M, the preparation is reported in Bioorg. Med. Chem. 2011 , 19 , 156). Triethylamine (0.019 mL, 0.136 mmol) was then added and the mixture was stirred at rt for 40 h. The solvent was blown off under a positive pressure of nitrogen to give a crude product as a white solid. The crude product was purified by MDAP (Method A) which gave the product in two portions and the second portion contained the pure product. This fraction was concentrated in vacuo to give a colorless gum-( R )-N-(1-(2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-benzene. [d] Imidazol-5-carbonyl)hexahydropyridin-3-yl)-2-chloroacetamidine (3.1 mg, 5.75 μmol, 12.69% yield).

LCMS (Method A): Rt = 1.17 min, MH ⁺ = 539.2

Example 79: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(7-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazol-5-yl)methanone

7-Ethyl-1H-indole-2-carboxylic acid (41 mg, 0.217 mmol, purchased from, for example, ACB Blocks) and HATU (90 mg, 0.237 mmol) were combined in DMF (1.0 mL) to give a yellow solution. The solution was allowed to stand at ambient temperature for about 5 min and then added to ( R )-(1-(3-amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl)carbamic acid A solution of the third butyl ester (75 mg, 0.215 mmol) and DIPEA (112 μL, 0.237 mmol) in DMF (1.0 mL). The resulting yellow solution was allowed to stand at ambient temperature (air atmosphere) for about 4 h. The reaction was diluted with water and extracted with DCM (×3). The combined organic extracts were dried (hydrophobic glass) and reduced to dryness under a stream of nitrogen to yield a brown oil. The oil was treated with p-toluenesulfonic acid (45 mg, 0.237 mmol) in toluene (5.0 mL) and heated at reflux for about 6 h. The reaction was carried out at ambient temperature overnight, diluted with MeOH and filtered over EtOAc EtOAc. The SPE was washed with methanol and the combined filtrate and washings were reduced to dryness under a stream of nitrogen. The residue was dissolved in DMSO / methanol (1:1, 1 mL) and purified by MDAP (Method A). The appropriate portion is reduced to dryness under a nitrogen stream. The residue was dissolved in DCM and washed with water. The organic phase is dried (hydrophobic glass) and reduced to dryness under nitrogen flow to yield ( R )-(3-aminohexahydropyridin-1-yl)(2-(7-ethyl-1H-indole) Indole-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (24 mg).

LCMS (Method B): Rt 0.80 min, MH ⁺ 402

Example 80: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-5,6-dimethoxy-1H-indol-2-yl)-1- Methyl-1H-benzo[d]imidazol-5-yl)methanone.

In a manner similar to that of Example 79, lithium salt of 1-ethyl-5,6-dimethoxy-1H-indole-2-carboxylate and ( R )-(1-(3-amino-4-(-) Preparation of tert-butyl ester of benzylamino)benzimidyl)hexahydropyridin-3-yl)carbamate.

LCMS (Method B): Rt = 0.68 min, MH ⁺ = 462.2

Example 81: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(3-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazol-5-yl)methanone

3-Ethyl-1H-indole-2-carboxylic acid (41 mg, 0.217 mmol, available from, for example, ABCR Product List) and HATU (90 mg, 0.237 mmol) were combined in DMF (1 mL) to give a brown solution. The mixture was stirred at ambient temperature for about 5 min and then ( R )-(1-(3-amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl)carbamic acid A solution of tributyl ester (75 mg, 0.215 mmol) and DIPEA (112 [mu]L, 0.646 mmol) in DMF (1 mL). The resulting brown solution was stirred at ambient temperature (air atmosphere) for about 1 h and then left at ambient temperature for one week. The reaction was diluted with water and extracted with DCM (×3). The combined organic extracts were dried (hydrophobic glass) and reduced to dryness under a stream of nitrogen to yield a brown oil.

A portion (60 mg) of this oil was treated with p-toluenesulfonic acid monohydrate (30 mg, 0.158 mmol) in toluene (5 mL) and the mixture was heated under reflux for about 4 h and then allowed to stand overnight at ambient temperature. The reaction was diluted with methanol to give a solution and filtered with EtOAc (EtOAc). The SPE was washed with methanol and the combined filtrate and washings were reduced to dryness under nitrogen to give sapphire glass (26 mg).

The remaining oil was treated with p-toluenesulfonic acid monohydrate (30 mg, 0.158 mmol) in toluene (5 mL) and the mixture was heated to reflux for 4 h and allowed to cool to ambient temperature overnight. The reaction was diluted with methanol to give a solution and filtered with EtOAc (EtOAc). The SPE was washed with methanol, the filtrate and washing were combined with the previously produced glass and the resulting solution was reduced to dryness under a stream of nitrogen. The residue was dissolved in DMSO / methanol (1:1, 1 mL) and purified by MDAP (Method A). The appropriate portion is reduced to dryness under a nitrogen stream. The residue was dissolved in DCM and washed with water. The organic phase is dried (hydrophobic glass) and reduced to dryness under nitrogen flow to yield ( R )-(3-aminohexahydropyridin-1-yl)(2-(3-ethyl-1H-indole-) 2-Based 1-methyl-1H-benzo[d]imidazol-5-yl)methanone (10 mg).

LCMS (Method B): Rt = 0.74 min, MH ⁺ = 402

Example 82: 1-{[2-(1-Ethyl-7-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3- Hexahydropyridinium

(1-{[2-(1-ethyl-7-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexa Hydrogen pyridyl)1,1-dimethylethylcarbamate (105 mg, 0.204 mmol) was treated with hydrogen chloride (4M, 2 mL, 8.0 mmol) from 1,4-dioxane and mixture was taken at ambient temperature Stir for about 2 hours. The volatiles were evaporated under a stream of nitrogen and the residual pink solid was dissolved in methanol. The solution was filtered through aminopropyl SPE (2 g). The SPE was washed with methanol and the combined filtrate and washings were reduced to dryness under a nitrogen stream to give a succulent gum-like 1-{[2-(1-ethyl-7-methyl-1H-indole-2-) 1-methyl-1H-benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine.

LCMS (Method B): Rt 0.82 min, MH ⁺ 416

Example 83: N-(2-Aminoethyl)-1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazole-5-A Guanamine

In a manner analogous to Example 82 from {2-[({1-methyl-2-[1-(phenylmethyl)-1H-indol-2-yl]-1H-benzimidazol-5-yl) Preparation of 1,1-dimethylethyl ester of carbonyl)amino]ethyl}aminocarbamate

LCMS (Method B): Rt = 0.97 min, MH ⁺ = 424

Example 84: 1-{[2-(1-ethyl-5-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3- Hexahydropyridinium

In a similar manner to Example 82, from (1-{[2-(1-ethyl-5-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl) Preparation of 1,1-dimethylethyl carbonyl}-3-hexahydropyridyl)carbamate

LCMS (Method B): Rt = 0.87 min, MH ⁺ = 416

Example 85: 1-{[2-(1-Ethyl-4-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-3- Hexahydropyridinium

In a manner analogous to Example 82 from (1-{[2-(1-ethyl-4-methyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl) Preparation of 1,1-dimethylethyl carbonyl}-3-hexahydropyridyl)carbamic acid.

LCMS (Method B): Rt = 0.85 min, MH ⁺ =416

Example 86: ( R )-2-(5-(3-Aminohexahydropyridine-1-carbonyl)-1-methyl-1H-benzo[d]imidazol-2-yl)-1-ethyl- 1H-吲哚-5-carbonitrile

To 5-cyano-1-ethyl-1H-indole-2-carboxylic acid (61.5 mg, 0.287 mmol), HATU (120 mg, 0.316 mmol) in N,N-dimethylformamide (DMF) (5 mL DIPEA (0.150 mL, 0.861 mmol) was added to the solution, followed by the addition of ( R )-(1-(3-amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl The third butyl carbamate (100 mg, 0.287 mmol) was stirred at rt for 2 h under nitrogen. Additional 5-cyano-1-ethyl-1H-indole-2-carboxylic acid (13.2 mg) was added and the mixture was aged for 16 h (overnight). The reaction mixture was diluted with water and extracted with DCM×3. The combined organics were washed with brine (× 3), dried over Na ₂ SO ₄ dried, and the volatiles were removed under reduced pressure to afford 150mg dark yellow oil. The oil was treated with p-toluenesulfonic acid monohydrate (60 mg, 0.315 mmol) in toluene (10 mL) and the solution was refluxed for 6h then rt and aging overnight. The mixture was loaded onto a pre-equilibrated NH of 20g ₂ column and eluted with MeOH (3CV) elution. The methanol fractions were combined and the volatiles were removed under reduced pressure to give 66 mg crude. By silica gel chromatography on 10g Si SNAP column using 20 CV of DCM and within a gradient of MeOH in 20% 2M NH ₃ The crude was purified. The relevant fractions were combined and the volatiles were removed under reduced pressure to give 35 mg of crude material. This material was purified by MDAP (Method A). The relevant fractions were combined and the volatiles were removed under reduced pressure to give ( R )-2-(5-(3-aminohexahydropyridine-1-carbonyl)-1-methyl-1H-benzo[d] Imidazolyl-2-yl)-1-ethyl-1H-indole-5-carbonitrile (4.1 mg, 9.61 μmol, 3.35% yield).

LCMS: (Method B) Rt 0.73 min, MH+ = 427.1.

Example 87: 2-(1-Ethyl-1 H -indol-2-yl)-1-methyl- N- (hexahydropyridin-3-yl)-1 H -benzo[ d ]imidazole-5 -Procarbamide

A mixture of HATU (385 mg) and 2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazole-5-carboxylic acid (294 mg) was suspended in Anhydrous DMF (4.5 mL) was taken and treated with DIPEA (0.324 mL). The mixture was sonicated and the resulting solution was allowed to stand in a stoppered container for 15 min at rt. The reaction mixture was homogeneously distributed (0.8 mL) into 6 containers. One vessel contained 3-aminohexahydropyridine-1-carboxylic acid tert-butyl ester (62 mg, 0.310 mmol, available from, for example, ABCR) and the reaction was allowed to stand in a stoppered vessel for 15 h. The reaction mixture was evaporated in a vacuum centrifuge. The gum was dissolved in EtOAc (1.0mL) and washed sequentially with aqueous 0.5M HCl (1mL), washed with saturated aqueous NaHCO ₃ (1 mL) and water (1mL). The organic layer was dried over a hydrophobic glass and the solvent was evaporated under a nitrogen stream. The gel was purified by MDAP (Method B). The appropriate fractions were combined and the solvent was evaporated in vacuo. The gum was dissolved in dry 1,4-dioxane (0.3 mL). The reaction mixture was allowed to stand in a stoppered vessel for 1 h and evaporated under a nitrogen stream. The solid was dissolved in MeOH (0.5 mL) and applied to MeOH &lt The column was washed with EtOAc (5 mL)EtOAc.

LCMS (Method B): Rt: 0.80min, MH + 402.

Example 88: ( S )-(3-(Aminomethyl)pyrrolidin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazol-5-yl)methanone

In a manner analogous to Example 87 from 2-(1-ethyl- 1H -indol-2-yl)-1-methyl- 1H -benzo[ d ]imidazole-5-carboxylic acid and ( R )- (Pyrrolidin-3-ylmethyl)carbamic acid tert-butyl ester (available from, for example, Astatech) was prepared.

LCMS (Method B): Rt: 0.76min, MH + 402.

Example 89: (2-(1-Ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazol-5-yl)(3-(methylamino) Hexahydropyridin-1-yl)methanone

2-(1-Ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazole-5-carboxylic acid (210 mg, 0.658 mmol), HATU (275 mg, 0.723 mmol) DIPEA (0.345 mL, 1.973 mmol) was added to a round bottom flask. Then DMF (3.5 mL) was added and the~~~~~~~ The reaction solution was evenly distributed between the three containers. One vessel contained 1,1-dimethylethyl methyl (3-hexahydropyridyl)carbamate (51.7 mg, 0.241 mmol, available from, for example, Activate Scientific) and was reacted at rt for 2 h. The sample was diluted with H ₂ O (1mL) and extracted with EtOAc (3 × 1mL), and the combined organics were evaporated under a stream of solvent in a nitrogen purge. The sample was dissolved in 1:1 MeOH: DMSO (1 mL) and purified by MDAP (Method B). The solvent was evaporated in vacuo. 4M HCl (0.5 mL) in 1,4-dioxane was added and allowed to react at rt for 30 min. The solvent was removed in vacuo under nitrogen to give the title compound (6 mg, 6%).

LCMS (Method B): Rt: 0.81min, MH + 416.

Example 90: N- (2-Aminoethyl)-2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazole-5- Formamide

In a manner analogous to Example 89 from 2-(1-ethyl- 1H -indol-2-yl)-1-methyl-1 H -benzimidazole-5-carboxylic acid and (2-aminoethyl) A 1,1-dimethylethyl carbamic acid ester (available, for example, from Fluorochem) was prepared.

LCMS (Method B): Rt: 0.78min, MH + 362.

Example 91: (3,4- cis )-1-{[2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl Carbonyl}-3,4-hexahydropyridinediamine (single mirror image isomer with cis- relative stereochemistry and unknown absolute stereochemistry).

To N,N'-((3,4-cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole -5-carbonyl) hexahydropyridine-3,4-diyl) bis(2,2,2-trifluoroacetamide) (31 mg, 0.051 mmol) in methanol (1.2 mL) / water (0.4 mL) Potassium carbonate (34.8 mg, 0.252 mmol) was added to the solution and the mixture was stirred at 60 ° C overnight under nitrogen. The reaction mixture was added directly to a 5 g SCX column. The column was eluted with MeOH (3 column volumes) and the product was eluted to the free base using 2M ammonia (3 column volume) in methanol. The product fraction was concentrated under vacuum and then dissolved in a minimum volume of MeOH and transferred to a vial. The solvent was removed under nitrogen and dried under vacuum overnight to give (3,4- cis )-1-{[2-(1-ethyl- 1H -indol-2-yl)-1-yl Base-1 H -benzimidazol-5-yl]carbonyl}-3,4-hexahydropyridinediamine (20 mg, 93%).

LCMS (high pH): Rt = 0.87 min, MH ⁺ = 417.2.

Example 92: (+/-)-((cis)-4-amino-2-methylpyrrolidin-1-yl)(2-(1-ethyl-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

To N -((cis)-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-5 Add methyl K ₂ CO ₃ (44.4) to a solution of methylpyrrolidin-3-yl)-2,2,2-trifluoroacetamide (33 mg, 0.066 mmol) in methanol (5 mL) and water (2.5 mL) Mg, 0.33 mmol) and the reaction was heated at 60 ° C for 3 h. The solvent was then concentrated in vacuo and the residue was partitioned between DCM and water (×3). The organic layer was dried (Na ₂ SO ₄₎ and concentrated in vacuo to give the crude product. This product was purified by MDAP (Method A). The appropriate fraction is concentrated in vacuo to give the desired free base. This base was dissolved in DCM (1mL) and add HCl (18μL, 0.036mmol, 2M in Et ₂ O in). The suspension was sonicated and allowed to stand 5min 15min, then the solvent was removed under a stream of N _2, to give the title compound (17.1mg).

LCMS (Method B): rt = 0.74 min.

Example 93: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1,7-dimethyl-1H-benzene And [d]imidazol-5-yl)methanone

To 2-(1-ethyl-1H-indol-2-yl)-1,7-dimethyl-1H-benzo[d]imidazole-5-carboxylic acid (6 mg, 0.018 mmol), ( R )- Add tributyl hexahydropyridin-3-ylaminocarbamate (33.9 mg, 0.169 mmol) and HATU (25.3 mg, 0.067 mmol) in a mixture of N,N-dimethylformamide (1 mL) DIPEA (39.2 [mu]L, 0.225 mmol). The reaction mixture was flushed with a pad of EtOAc (EtOAc m.). The appropriate fractions were combined and dried under a stream of nitrogen to give a brown gum. The gum was dissolved in DMSO (0.5 ml) and purified by MDAP (Method B). The solvent was dried under a stream of nitrogen to produce a colorless gum. Dichloromethane (0.8 mL) was added followed by trifluoroacetic acid (200 mL, 2.60 mmol) The reaction mixture was flushed with a pad of EtOAc (EtOAc m.). The appropriate fractions are combined and dried under nitrogen to give the desired product ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indole-2-) 1,7-Dimethyl-1H-benzo[d]imidazol-5-yl)methanone (4.3 mg, 10.35 μmol, 57.5% yield).

LCMS (Method B): Rt 0.79 min, MH.

Example 94: ( R )-(3-Aminohexahydropyridin-1-yl)(1-(3-aminopropyl)-2-(1-ethyl-1H-indol-2-yl)- 1H-benzo[d]imidazol-5-yl)methanone, bis -hydrochloride

To ( R )-(1-(1-(3-aminopropyl)-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5-carbonyl To a third butyl hexahydropyridin-3-yl)carbamate (25 mg, 0.046 mmol) was added 4 M hydrochloric acid ( 918 uL, 3.67 mmol) in 1,4-dioxane and the mixture was stirred at rt. After 6 h, it was evaporated to dryness under a nitrogen stream to leave the desired product ( R )-(3-aminohexahydropyridin-1-yl)(1-(3-aminopropyl)-2-(1- Ethyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, bis -hydrochloride (15 mg, 0.029 mmol, 63.2% yield).

LCMS (Method A): Rt = 0.80 min, MH ⁺ = 445.

Example 95: ( R )-(3-Aminohexahydropyridin-1-yl)(1-ethyl-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d Imidazol-5-yl)methanone, hydrochloride

( R )-(1-(1-ethyl-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d] in 1,4-dioxane (3 mL) Addition of 4M Hydrochloric Acid (1 mL, 4.00 mmol) in 1,4-dioxane to a third butyl ester of imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamate (140 mg, 0.272 mmol) 2h. The reaction mixture was evaporated to dryness under nitrogen flow, triturated with ether (2mL), filtered and dried in a vacuum oven to leave ( R )-(3-aminohexahydropyridin-1-yl) (1-B 2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (98 mg, 0.217 mmol, 80% yield) .

LCMS (Method B): Rt = 0.84 min, MH.

Example 96: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-3-methyl-3H-imidazo[4 ,5-b]pyridin-6-yl)methanone, hydrochloride

In a manner analogous to Example 95 from ( R )-(1-(1-ethyl-2-(1-ethyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5- Preparation of carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt = 0.779 min.

Example 97: trans (+/-)-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-yl Base-1 H -benzo[ d ]imidazol-5-yl)methanone.

Trans (+/-)(1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ d ]imidazole-5-carbonyl) a solution of 4-fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester (45 mg, 0.087 mmol) in anhydrous 1,4-dioxane (0.4 mL) using HCl (4M in EtOAc -dioxane (0.4 mL, 1.600 mmol) was worked up and stirred at rt for 1 h. The reaction mixture was evaporated in vacuo andqqqq eluted The solution was applied to a MeOH pre-conditioned 1 g SCX-2 column which was washed with MeOH (6 mL) then 2M ammonia (6 mL) in MeOH. The alkaline wash was evaporated under a stream of nitrogen and the gum was dissolved in ether. The solvent was removed under a nitrogen stream and the solid was dried in vacuo to afford titled compound (33mg,

LCMS (Method B): Rt: 0.82min, MH + 420.

Example 98: cis -((+/-)-3-amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1- Methyl-1H-benzo[d]imidazol-5-yl)methanone.

From cis -(+/-)-(1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo) in a similar manner to Example 97 Preparation of [d]imidazole-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester

LCMS (Method B): Rt = 0.79 min, MH ⁺ = 418.2

Example 99: trans -((+/-)-3-Amino-4-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1- Methyl-1H-benzo[d]imidazol-5-yl)methanone.

The manner analogous to Example 97 from trans (+/-) - (1- (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H- benzo [d] Preparation of tert-butyl ester of imidazole-5-carbonyl)-4-hydroxyhexahydropyridin-3-yl)carbamic acid

LCMS (Method B): Rt = 0.74 min, MH ⁺ = 418.2

Example 100: cis( +/-)-3-amino-4-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1 -Methyl-1 H -benzo[ d ]imidazol-5-yl)methanone.

In a manner analogous to Example 97 from cis( +/-)-(1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[ Preparation of d ]imidazole-5-carbonyl)-4-methoxyhexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt: 0.84min, MH + 432.

Example 101: (3 R )-1-{[2-(7-Bromo-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl Carbonyl}-3-hexahydropyridinium

A solution of 7-bromo-1-ethyl-1 H -indole-2-carboxylic acid (300 mg, 1.12 mmol) and HATU (468 mg, 1.23 mmol) in DMF (2 mL) was stirred at rt for about 5 min. To this was added ((3 R )-1-{[3-amino-4-(methylamino)phenyl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1-dimethyl A solution of ethyl ester (390 mg, 1.12 mmol) and EtOAc (EtOAc) The mixture was partitioned between EtOAc (EtOAc)EtOAc. The combined organic layers were passed through a hydrophobic glass, then concentrated under reduced pressure and azeotroped with toluene to give crude decylamine intermediate. The crude material was dissolved in toluene (12.5 mL) and acetic acid (0.070 mL, 1. The reaction mixture was refluxed for 5 h then stirred for additional 48 h and then concentrated. The crude material was loaded onto a SCX-II SPE column in MeOH and then taken up with MeOH and then 2M ammonia in MeOH. The desired product was dissolved in a combined portion of ammonia and then concentrated under reduced pressure to yield s. The title compound (300 mg, 56%) eluted elute elut elut elut elut elut

LCMS (Method B): MH+ = 480.1 / 482.1, Rt = 0.88 min

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm: 7.85-7.76 (m, 3H), 7.59 (d, 1H), 7.44 (d, 1H), 7.19 (s, 1H), 7.13 (dd, 1H) , 4.90 (q, 2H), 4.41-4.04 (m, 1H), 3.98 (s, 3H), 3.87-3.41 (m, 1H), 3.08-2.93 (m, 1H), 2.83-2.64 (m, 2H) , 1.99-1.86 (m, 1H), 1.79-1.59 (m, 2H), 1.58-1.48 (m, 1H), 1.34 (t, 3H)

Example 102: 2-(5-{[(3 R )-3-Amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1-B Base-1 H -吲哚-7-ol

(3 R )-1-({2-[1-ethyl-7-(methyloxy)-1 H -indol-2-yl]-1-methyl-1 H -benzene under nitrogen And imidazolium-5-yl}carbonyl)-3-hexahydropyridylamine (61 mg, 0.14 mmol) in DCM (1.5 mL) and cooled to about 0 ° C dropwisely added boron tribromide solution (1M in DCM) Medium, 0.14 mL, 0.14 mmol). The reaction mixture was stirred in an ice water bath for 15 min then warmed to rt and kept for 1.5 h. MeOH (5 mL) was added, then the mixture was concentrated under reduced pressure. The mixture was taken up in EtOAc EtOAc EtOAc (EtOAc).

LCMS: (Method A) Rt = 0.83 min, MH+ = 418.3

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm: 9.86 (br.s., 1H), 7.78-7.69 (m, 2H), 7.37 (d, 1H), 7.11 (d, 1H), 6.94 (s , 1H), 6.90 (dd, 1H), 6.66 (d, 1H), 4.75 (q, 2H), 4.41-4.08 (m, 1H), 3.93 (s, 3H), 3.80-3.48 (m, 1H), 3.08-2.87(m,2H),2.84-2.65(m,2H),1.95-1.82(m,1H),1.78-1.59(m,1H),1.54-1.37(m,1H),1.24(t,3H )

Example 103: 2-(5-{[(3 R )-3-Amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1-( Cyclopropylmethyl)-1 H -indol-5-ol.

( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-5-methoxy-1H-indol-2-yl)-1- Methyl-1H-benzo[d]imidazol-5-yl)methanone (56 mg, 0.122 mmol) was dissolved in dichloromethane <RTI ID=0.0> Boron tribromide (0.122 mL, 0.122 mmol) was added dropwise and the mixture was stirred 1 h. The reaction was warmed to 0 ° C and stirred for additional 1 h. A further aliquot of boron tribromide (0.244 mL, 0.244 mmol) was added and the mixture was warmed to rt and stirred for 1 h. A further aliquot of boron tribromide (0.244 mL, 0.244 mmol) was added and the reaction was stirred for additional 1 h. The reaction was quenched with MeOH (5 mL) and concentrated in vacuo. An additional amount of MeOH (5 mL) was added and the solvent was removed again in vacuo. The crude product was dissolved in MeOH and directly added to a 2 g SCX column. This was dissolved in methanol (3 column volumes) and the product was eluted to the free base using 2M ammonia in methanol. The filtrate from the ammonia fraction was concentrated in vacuo to give a crude product as a green oil. The crude product was further purified by MDAP (Method A). The appropriate fractions from MDAP were combined and concentrated in vacuo to give product (-( R )-(3-aminohexahydropyridin-1-yl)(2-(1-cyclopropylmethyl)- 5-Hydroxy-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (32 mg, 0.072 mmol, 58.9% yield).

LCMS (Method B): Rt = 0.64 min, MH ⁺ = 444.2

Example 104: 2-(5-{[(3 R )-3-Amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1-B Base-1 H -吲哚-6-alcohol.

In a similar manner to Example 103 from ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-ethyl-6-methoxy-1H-indol-2-yl)- 1-Methyl-1H-benzo[d]imidazol-5-yl)methanone was prepared in 86% yield.

LCMS (Method A): Rt = 0.78 min, MH ⁺ = 418.2

Example 105: ( 3R )-1-{[2-(1-Ethyl-7-fluoro-1 H -indol-2-yl)-1-methyl-1 H -benzimidazol-5-yl ]carbonyl}-3-hexahydropyridinamine.

Add to a solution of 1-ethyl-7-fluoro-1 H -indole-2-carboxylic acid (89 mg, 0.43 mmol) and HATU (180 mg, 0.47 mmol) in DMF (2 mL) (1 R 1 -{[3-Amino-4-(methylamino)phenyl]carbonyl}-3-hexahydropyridyl)carbamic acid 1,1-dimethylethyl ester ( 150 mg, 0.43 mmol) and a solution of DIPEA (0.225 ml, 1.29 mmol) in DMF (2 mL). The reaction mixture was stirred under nitrogen for 2h at rt, followed by adding l-ethyl-7-fluoro -1 H - indole-2-carboxylic acid (89mg, 0.43mmol) and HATU (180mg, 0.47mmol) and the reaction The mixture was stirred for a further 17 h and then concentrated under reduced pressure. The crude material was loaded onto a SCX SPE column and eluted with MeOH then 2N ammonia in MeOH. The guanamine intermediate is expected to be dissolved in the ammonia fraction, combined, and then concentrated under reduced pressure, followed by azeotrope with cyclohexane to give the crude guanamine intermediate as a cream solid.

A solution of 4-toluenesulfonic acid monohydrate in acetic acid (0.056 mL, 0.32 mmol) and toluene (10.0 mL).

The mixture was concentrated under reduced pressure and DCM (3 mL) andEtOAc. The reaction mixture was stirred at rt EtOAc 40 min. The mixture was loaded onto a SCX SPE column in MeOH and the column was eluted with MeOH then 2M ammonia in MeOH. The desired product was dissolved in a combined ammonia-based portion, which was then concentrated under reduced pressure to give a brown oily crude product which solidified upon standing. The title compound (63 mg) was obtainedjjjjjjj Impurities are retained and, therefore, the material is purified again by MDAP (Method C). The material was loaded onto a SCX SPE column in MeOH and the column was eluted with MeOH then 2M ammonia in MeOH. The title compound (37 mg, 18%) was obtained.

LCMS (Method C): MH+ = 420.1, Rt = 0.77 min

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm: 7.82-7.68 (m, 2H), 7.57-7.48 (m, 1H), 7.38 (d, 1H), 7.20-7.06 (m, 3H), 4.63 ( q, 2H), 4.43-4.09 (m, 1H), 3.97 (s, 3H), 3.76-3.21 (m, 2H), 3.07-2.55 (m, 2H), 2.32-2.09 (m, 1H), 1.95- 1.81(m,1H),1.80-1.56(m,1H),1.55-1.38(m,1H),1.34(t,3H)

Example 106: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-4-fluoro-1H-indol-2-yl)-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone.

Add HATU to a solution of 1-ethyl-4-fluoro-1H-indole-2-carboxylic acid (25 mg, 0.121 mmol, available from, for example, Apollo Scientific) in N,N -dimethylformamide (2 mL) (50.5 mg, 0.133 mmol) and DIPEA (0.063 mL, 0.362 mmol). The mixture was stirred for a few minutes, followed by the addition of ( R )-(1-(3-amino-4-(methylamino)benzylidenyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester (42.0 mg, 0.121 mmol). The reaction was allowed to proceed overnight at rt then concentrated under reduced pressure. The residue was dissolved in DMF (2 mL) and EtOAc (EtOAc:EtOAc. The reaction was heated to 110 ° C for 3 h then concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc) (EtOAc)

LCMS (Method B): Rt = 0.80 min, MH ⁺ = 420.2

Example 107: 2-(5-{[(3 R )-3-Amino-1-hexahydropyridinyl]carbonyl}-1-methyl-1 H -benzimidazol-2-yl)-1-B Base-1 H-吲哚-7-carbonitrile

(3 R )-1-{[2-(7-bromo-1-ethyl-1 H -indol-2-yl)-1-methyl-1 H - under nitrogen in a dry 2 mL microwave vial Zinc cyanide (100 mg, 0.85 mmol) was added to a stirred solution of benzimidazol-5-yl]carbonyl}-3-hexahydropyridinamine (50 mg, 0.104 mmol) in DMF (1 mL). Palladium tetratriphenylphosphine (15 mg, 0.013 mmol) was added to the reaction mixture and the vial was heated at 110 ° C for 2 h using microwave. Additional tetrapalladium (15 mg, 0.013 mmol) was added and the reaction mixture was heated at 110 ° C for additional 2 h. The crude mixture was loaded onto a SCX-II SPE column in MeOH, washed with MeOH and then eluted with 2N ammonia in MeOH. The desired product was isolated in the combined ammonia / MeOH portion and then concentrated under reduced pressure to afford crude product which was purified by MDAP (Method A). The title compound (15.4 mg, 35%) was obtained.

LCMS (Method B): MH+ = 427.2, Rt = 0.79 min

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.10 (d, 1 H), 7.82 (d, 1 H), 7.79-7.68 (m, 2 H), 7.39 (d, 1 H), 7.36-7. (m, 2 H), 4.81 (q, 2 H), 4.43-4.01 (m, 1 H), 3.96 (s, 3 H), 3.75-3.45 (m, 1 H), 3.03-2.86 (m, 1) H), 2.81-2.58 (m, 2 H), 1.93-1.81 (m, 1 H), 1.78-1.57 (m, 2 H), 1.42 (t, 3 H), 1.37-1.12 (m, 1 H)

Example 108: (5-Amino-5,6-dihydropyridine-1( 2H )-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl- 1 H -benzo[ d ]imidazol-5-yl)methanone

(5-azido-5,6-dihydropyridine-1(2 H )-yl)(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 Triphenylphosphine (66 mg, 0.252 mmol) was added to a stirred solution of H -benzo[ d ]imidazol-5-yl)methanone (71.4 mg, 0.168 mmol) in THF (8 mL). ). After 66 h, the mixture was heated to reflux for 2 min then cooled to rt. After a further 21 h, the mixture was concentrated in vacuo. Water was added to the residue and potassium dihydrogen phosphate was added to bring the solution to pH 4. The mixture was extracted with EtOAc (×3). The aqueous was then extracted with DCM and basified with NaHCO _3. The DCM extracts were then dried (Na ₂ SO _4), filtered, and concentrated in vacuo to give a residue. The residue was taken up in EtOAc EtOAc (EtOAc m.

LCMS (Method B): Rt = 0.78 min, MH ⁺ = 400.1

Example 109: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-(3-hydroxypropoxy)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone.

To ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Add 3-((tert-butyldimethylmethyl)oxy)propane to a solution of dihydrobutylpyridin-3-yl)carbamate (50 mg, 0.097 mmol) in THF (2 mL) 1-Alcohol (0.041 mL, 0.194 mmol) and triphenylphosphine (51 mg, 0.194 mmol). The mixture was flushed with nitrogen, then cooled to about 0 ° C using an ice/water bath and then di-diphenylene-1,2-dicarboxylic acid di-t-butyl ester (45 mg, 0.195 mmol) in THF (2 mL). Solution. The mixture was stirred at rt for 20 h then THF (4 mL). Additional 3-((t-butyldimethylmethyl)oxy)propan-1-ol (0.041 mL, 0.194 mmol) was added followed by triphenylphosphine (51 mg, 0.194 mmol) and azodicarboxylic acid -T-butyl ester (45 mg, 0.195 mmol) and the mixture was stirred for 4.5 h. The mixture was concentrated under reduced pressure to give a crude material. This material was dissolved in DCM (3 mL) then TFA (3 mL) was then evaporated. The mixture was stirred for 30 min then concentrated under reduced pressure and EtOAc m m m m m m m The mixture was loaded onto a SCX SPE column and the column was eluted with methanol (3M) in methanol. The fractions containing the desired product were combined, EtOAcjjjjjjjjjjj .

LCMS (Method B): Rt = 0.95 min, MH ⁺ = 476.3

Example 110: ( R )-(3-Aminohexahydropyridin-1-yl)(7-ethoxy-2-(1-ethyl-1H-indol-2-yl)-1-methyl- 1H-benzo[d]imidazol-5-yl)methanone

To ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Add a solution of triethyl butyl pyridin-3-yl)carbamate (50 mg, 0.097 mmol) in THF (2 mL) EtOAc. Mm). The mixture was flushed with nitrogen, then cooled to about 0 °C using an ice/water bath and then diazene-1,2-dicarboxylic acid di-t-butyl ester (45 mg, 0.195 mmol) was added dropwise to the mixture. Solution in THF (2 mL). The reaction mixture was stirred at rt for 16 h then diazene-1,2-dicarboxylic acid di-t-butyl ester (45 mg, 0.195 mmol), triphenylphosphine (51 mg, 0.194 mmol) and EtOH (11 μL) , 0.195 mmol) and the mixture was stirred for additional 16 h under nitrogen. The reaction mixture was concentrated with EtOAc EtOAc m. The reaction mixture was stirred under nitrogen for 2 h then concentrated EtOAc. This material was dissolved in a 1:1 mixture of EtOAc and MeOH (EtOAc)

LCMS (Method B): Rt = 0.90 min, MH ⁺ = 446.2

Example 111: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-(2-methoxyethoxy) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone.

In a manner analogous to Example 110 from ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d] Preparation of imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester and 2-methoxyethanol.

LCMS (Method B): Rt = 0.84 min, MH ⁺ = 476.3

Example 112: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-(2-hydroxyethoxy)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone.

To ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Add (2-bromoethoxy)(t-butyl)dimethyl decane (2 -Bromoethoxy)(t-butyl)dimethyl decane to a solution of tributyl butyl pyridin-3-yl)carbamate (50 mg, 0.097 mmol) in DMF (5 mL) 21 μL, 0.098 mmol) and cesium carbonate (63 mg, 0.193 mmol). The mixture was flushed with nitrogen and then stirred at rt for 17 h. The reaction mixture was concentrated under reduced br The aqueous layer was re-extracted with EtOAc (2×15 mL). The resultant was dissolved in EtOAc (2 mL)EtOAc. The reaction mixture was concentrated under reduced pressure and then applied to EtOAc EtOAc EtOAc. The product-containing fractions were combined with EtOAc EtOAc m.

LCMS (Method B): Rt = 0.91 min, MH ⁺ = 462.4

Example 113: ( R )-2-((5-(3-Aminohexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl- 1H-benzo[d]imidazol-7-yl)oxy)acetonitrile.

In a similar manner to Example 112 from ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d] Preparation of imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester and 2-bromoacetonitrile.

LCMS (Method A): Rt = 1.02 min, MH ⁺ = 457.3

Example 114: ( R )-2-((5-(3-Aminohexahydropyridine-1-carbonyl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl- 1H-benzo[d]imidazol-7-yl)oxy)acetamide.

In a similar manner to Example 112 from ( R )-(1-(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H-benzo[d] Preparation of imidazole-5-carbonyl)hexahydropyridin-3-yl)carbamic acid tert-butyl ester and 2-bromoacetamide.

LCMS (Method A): Rt = 0.88 min, MH ⁺ = 475.3

Example 115: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-7-hydroxy-1-methyl-1H- Benzo[d]imidazol-5-yl)methanone.

The 3-neck flask was dried (132 ° C) for 4 h. The flask was cooled under nitrogen, vented and backfilled 4 times, then charged with ( R )-(3-aminohexahydropyridin-1-yl) (2-(1-) dissolved in dichloromethane (2 mL) Ethyl-1H-indol-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazol-5-yl)methanone (59 mg, 0.137 mmol). The solution was cooled to 0 ° C, then boron tribromide (0.137 mL, 0.137 mmol) was added dropwise. The reaction mixture was placed in an ice bath for 20 min then warmed to rt. LCMS analysis showed partial conversion, therefore, the solution was cooled to 0 ° C and boron tribromide (0.137 mL, 0.137 mmol) was added. The resulting solution was warmed to rt. Additional boron tribromide (0.137 mL, 0.137 mmol) was added 5 more times in the same process until an increase in by-products was observed. The reaction was quenched by the slow addition of methanol (5 mL). An additional 5 mL of methanol was added and the solvent was removed under vacuum. The crude mixture was purified by EtOAc (EtOAc).

LCMS (Method B): Rt = 0.74 min, MH ⁺ = 418.1

Example 116: (+/-)-(3-Amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl -1H-benzo[d]imidazol-5-yl)methanone, trans- isomer.

N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)-4- at 50 °C Methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide, trans- isomer (140 mg, 0.274 mmol) in methanol (4 mL) and water (1 mL) with potassium carbonate ( 76 mg, 0.547 mmol) were stirred together for 20 h. The reaction mixture was partitioned between brine and DCM. The aqueous layer was further extracted with DCM. The organics were combined, passed through a pad of water and concentrated in vacuo. 10g Biotage SP4 by chromatography on silicon dioxide in the SNAP column with 12 column volumes of DCM and 0 to 10% 2M NH ₃ / MeOH elution residue was purified to give the desired product as a colorless oil (74 mg of, 65%).

LCMS (Method B): Rt 0.82min, m / z 416.1 (MH +)

Examples 117 and 118: trans- 3-amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H -Benzo[d]imidazol-5-yl)methanone, hydrochloride, single unknown mirror image isomer.

Chiral separation of trans- 3-amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl- from 80 mg mixture Two mirror image isomers of 1H-benzo[d]imidazol-5-yl)methanone (Method J) to produce two mirror image isomers:

• Image Enantiomer A: 20 mg (25%) was isolated by chirality, followed by HCl salt (15 mg, 69%).

○ LCMS (Method B): Rt = 0.81 min, MH ⁺ = 416.3

• Image Enantiomer B: 10 mg (13%) was isolated by chirality, followed by HCl salt (10.3 mg, 95%).

○ LCMS (Method B): Rt = 0.82 min, MH ⁺ = 416.4

Example 119: (+/-)-(3-Amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl -1H- benzo [d] imidazol-5-yl) methanone, cis - isomer.

In a similar manner to Example 116, from N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) 4-Methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide, cis- isomer preparation.

LCMS (Method B): Rt = 0.81min, MH + = 416.2

Example 120: cis- 3-amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene And [d]imidazol-5-yl)methanone, hydrochloride, a single unknown mirror image isomer.

Chiral separation of cis- 3-amino-4-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene And two mirror image isomers of [d]imidazol-5-yl)methanone (Method K) to give a second isolated isomer (77 mg, 28%) as a colorless oil. The oil was taken up in tetrahydrofuran (1 ml), and 1M hydrogen chloride (0.185 mL, 0.185 mmol) in diethyl ether was added to the solution. The suspension was stirred at rt for 5 min then concentrated to give a white solid.

LCMS (Method B): Rt = 0.80 min, MH ⁺ = 416.3

Example 121: (+/-)- cis- 5-amino-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-carbonyl) hexahydropyridine-3-carboxamide.

From cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) in a similar manner to Example 116 Preparation of 5-(2-(2,2,2-trifluoroacetamido)piperidine-3-carboxamide.

LCMS (Method B): Rt = 0.71 min, MH ⁺ = 445.1

Example 122: (3-Amino-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[ d] imidazolium-5-yl)methanone hydrochloride, a mixture of non-image isomers.

N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole in methanol (5 mL) and water (2.5 mL) -5-Carbonyl)-5-methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide (42 mg, 0.082 mmol) was added with K ₂ CO ₃ (56.7 mg, 0.411 mmol) The reaction was heated to 60 ° C for 2 h. The solution was concentrated in vacuo and partitioned between DCM and water (EtOAc) The organic layers were combined, the solvent was evaporated and the crude crystals were re-dissolved in DCM and purified on silica gel eluting with 0-10% 2M methanol in DCM. Combine the appropriate parts and remove the solvent. The residue was dried under high vacuum overnight to give a clear oil, which was dissolved in DCM (1mL) and 1.0M etheric HCl (12 μL). The solvent was removed to give the title compound (5 mg, 14%).

LCMS (Method B): rt = 0.82 min.

Example 123 and Example 124: cis - (3-amino-5-methyl-piperidine-1-yl) (2- (1-ethyl -1H- indol-2-yl) -1-methyl -1H-benzo[d]imidazol-5-yl)methanone hydrochloride, a single unknown mirror image isomer.

N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole) to methanol (10 mL) and water (5 mL) Addition of K ₂ CO ₃ (419 mg, 3.03 mmol) to 5-carbonyl)-5-methylhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide (310 mg, 0.606 mmol) The material was heated to 60 ° C for 4 h. The mixture was concentrated in vacuo and partitioned between DCM and brine (×2). The organic layers were combined and the solvent was removed to give a white foam solid. This material was isolated by chiral preparative HPLC (Method L). The residue was dissolved in EtOAc EtOAc (EtOAc)

Example 123: LCMS (Method B): MH+ = 41.

Example 124: LCMS (Method B): MH + = 416.3, Rt = 0.80min.

Example 125 and Example 126: trans- (3-Amino-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl -1H-benzo[d]imidazol-5-yl)methanone hydrochloride, a single mirror image isomer with unknown relative stereochemistry.

(3-azido-5-methylhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl- to ethanol (10 mL) added 1H- benzo [d] imidazol-5-yl) methanone (104mg, 0.236mmol) Pd (OH ) 2 (16.54mg, 0.024mmol) and the reaction was stirred at rt overnight under a hydrogen atmosphere. The suspension was filtered through celite and washed with ethanol and then solvent was removed. The residue was dissolved in DCM and loaded onto EtOAc (EtOAc) eluting eluting The appropriate fractions are combined and the solvent removed to produce a clear oil. The enantiomers were then separated by chiral preparative HPLC (Method M) and dissolved in DCM (1 mL) and etheric HCl (1.0M, 36 uL or 31 uL) was added. The solvent was removed to give a beige solid (9 mg, 8% and 10 mg, 9%).

Example 125: LCMS (Method B): Rt = 0.82min, MH + = 416.2.

Example 126: LCMS (Method B): Rt = 0.71 min.

Example 127: (3-Amino-5-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-yl)methanone, a mixture of non-image isomers.

N-(1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole) to methanol (10 mL) and water (5 mL) Addition of K ₂ CO ₃ (14.75 mg, 0.107 mmol) to 5-carbonyl)-5-fluorohexahydropyridin-3-yl)-2,2,2-trifluoroacetamide (11 mg, 0.021 mmol) The material was heated to 60 ° C for 4 h. The solution was concentrated in vacuo and partitioned between DCM and water (×2). The combined organic layers were evaporated and the residue was crystalljjjjjjjj The appropriate fractions were combined and the solvent removed to give a white film (5.1 mg, 57%).

LCMS (Method B): Rt = 0.78 min, MH+ = 420.1.

Example 128: (+/-)-((cis)-3,5-diaminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1 -Methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

cis- N,N'-(-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-) in methanol (10 mL) and water (5 mL) Addition of K ₂ CO ₃ (469 mg) to benzo[d]imidazol-5-carbonyl)hexahydropyridine-3,5-diyl)bis(2,2,2-trifluoroacetamide) (413 mg, 0.679 mmol) , 3.39 mmol) and the reaction was stirred at 60 ° C for 3 h. The solution was concentrated in vacuo and suspended in DCM and partitioned between DCM and water (×3). The residue was dried under high vacuum EtOAc (EtOAc) (EtOAc) The solvent was removed to give a pale yellow solid (148 mg, 48%).

LCMS (Method B): Rt = 0.70 min, MH+ = 417.2.

Example 129: (+/-)-(( trans )-3-amino-5-methoxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl) )-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride.

In a similar manner to Example 128, from N-(( trans )-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole Preparation of 5-5-carbonyl)-5-methoxyhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide.

LCMS (Method B): Rt = 0.779 min.

Example 130: (3-Amino-5-hydroxyhexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d Imidazole-5-yl)methanone, hydrochloride, a mixture of non-image isomers.

In a similar manner to Example 128, from N- (1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Preparation of 5-hydroxyhexahydropyridin-3-yl)-2,2,2-trifluoroacetamide.

LCMS (Method B): rt = 0.73 min.

Example 131: (+/-)- cis- 3-amino-1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazole-5-carbonyl) hexahydropyridine-4-carboxamide, hydrochloride.

In a similar manner to Example 128, from cis- 1-(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl) Preparation of -3-(2,2,2-trifluoroacetamido)hexahydropyridine-4-carboxamide

LCMS (Method B): Rt = 0.77 min, MH+ = 445.3.

Example 132: (3-Aminohexahydropyridin-1-yl)(1-methyl-2-(1-methyl-1H-indol-2-yl)-1H-benzo[d]imidazole-5 -based) ketone.

Add methylamine hydrochloride (6.75 mg, 100 μmol) and DIPEA (52.4 μL) to a solution of 4-fluoro-3-nitrobenzoic acid (18.51 mg, 100 μmol, purchased from Sigma-Aldrich) in EtOH (1 mL). , 300 μmol). The reaction mixture was stirred at 80 &lt;0&gt;C for 6 h and then concentrated. This was redissolved in DMF (1 mL) and treated with trihydropyridin-3-ylaminocarbamic acid tert-butyl ester (20.03 mg, 100 [mu]mol) and HATU (38.0 mg, 100 [mu]mol). The reaction mixture was stirred at rt overnight. Standard post-treatment yielded the guanamine which was dissolved in EtOH (1 mL), 1-methyl-1H-indole-2-carbaldehyde (15.92 mg, 100 μmol, purchased from Sigma-Aldrich, for example) in water (0.5 mL). Treated with sodium sulfoxylate (0.3 μmol, 65 mg). The reaction mixture was stirred at 85 ℃ overnight, cooled to rt, concentrated and partitioned between EtOAc / NaHCO _3. The organics were dried with EtOAc EtOAc m.

LCMS (Method B): Rt = 0.64 min, MH+ = 388.1.

Example 133: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-1-(2-methoxyethyl) -1H-benzo[d]imidazol-5-yl)methanone.

Solution of 4-fluoro-3-nitrobenzoic acid (18.51mg, 100μmol) was added in DMF (1 mL) in a solution of HATU (38.0mg, 100μmol) and DIPEA (52.4μL, 300μmol), after addition of (3 R) - 1,1-Dimethylethyl 3-hexahydropyridylaminocarbamate (20.03 mg, 100 μmol, available from, for example, Apollo Scientific). The reaction mixture was stirred at rt for 5 h and then worked-up to afforded &lt;RTI ID=0.0&0&gt ; . 2-Methoxyethylamine (7.51 mg, 100 μmol) and DIPEA (52.4 μL, 300 μmol) were added to the above-prepared guanamine in EtOH (1 mL). The reaction mixture was stirred at 60 ° C overnight, concentrated, EtOAc EtOAc (EtOAc m. Sodium (0.3 umol, 65 mg) was treated. The reaction mixture was stirred at 85 ℃ overnight, cooled to rt, concentrated and partitioned between EtOAc / NaHCO _3. The organics were dried, concentrated, purified with EtOAc EtOAc EtOAc

LCMS (Method B): Rt = 0.83 min, MH+ = 508.3.

Example 134: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-benzyl-1H-indol-2-yl)-1-isopropyl-1H-benzo[ d] imidazolium-5-yl)methanone.

To a solution of 4-fluoro-3-nitrobenzoic acid (18.51 mg, 100 μmol) in DMF (1 mL) was added HATU (45.6 mg, 120 μmol) and DIPEA (52.4 μL, 300 μmol). The reaction mixture was stirred at rt for 5 min and EtOAc &lt;RTI ID=0.0&gt;&gt ; Standard post-treatment produced guanamine (a 1/3 double addition was observed). The crude decylamine was dissolved in EtOH (1 mL) and EtOAc (EtOAc (EtOAc) (EtOAc) (EtOAc) Treatment with 1-benzyl-1H-indole-2-carbaldehyde (23.53 mg, 100 μmol) and sodium sulfoxylate (0.3 umol, 65 mg). The reaction mixture was stirred at 85 ℃ overnight, cooled to rt, concentrated and partitioned between EtOAc / NaHCO _3. The organics were dried, concentrated, purified with EtOAc EtOAc EtOAc

LCMS (Method B): Rt = 0.87 min.

Example 135: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d] Imidazol-5-yl)methanethione hydrochloride

To ((3 R )-1-{[2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzimidazol-5-yl]thiocarbenyl} A solution of 4N HCl in dioxane was added to a solution of EtOAc &lt;RTI ID=0.0&gt;&gt; The reaction mixture was concentrated in vacuo and Et ₂ O was added to the residue. The resulting precipitate was filtered, washed with ₂ O Et and dried in vacuo to yield the title compound as a yellow solid (74mg).

LCMS (Method A): Rt = 1.03 min.

Example 136: ( cis -(+/-)-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1 -methyl-1H-benzo[d]imidazol-5-yl)methanone

2-(1-Ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazole-5-carboxylic acid (110 mg, 0.344 mmol) in DMF (2 mL) HATU (157 mg, 0.413 mmol) was added to the stirred solution, followed by DIPEA (0.072 mL, 0.413 mmol). After stirring at rt for 30 min, ( cis -(+/-)-4-fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester (150 mg, 0.344 mmol) was added to this mixture and this Stir at rt for 2 h and allow to stand for 64 h without stirring. The solvent was removed under reduced pressure and water (10 mL) was added to the residue. The cream white precipitate was filtered off and rinsed with water (2×5 mL). The precipitate was dried in a vacuum oven for 2 h to give 220 mg (123%) of cream solid (product of Boc protection). A small amount of cream solid was purified by MDAP (Method A). The appropriate portion was transferred to a vial and the volatiles were removed under reduced pressure to afford the desired intermediate decylamine (3.2 mg) which was still protected with Boc and chiral separation. The bulk of the remaining Boc protected product was taken up in DCM (5 mL After stirring at rt for 30 min, the solvent was removed under reduced pressure and the dark purple residue was taken in MeOH to EtOAc (EtOAc). The column was washed with MeOH (3 CV) and product was eluted with methanol (2N) (3 CV). The ammonia fraction was combined and evaporated under reduced pressure. The residue (189 mg) was loaded onto a 10 g SNAP s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Appropriate fractions were combined and evaporated in vacuo to crystall

LCMS (Method B): Rt = 0.78 min, MH+ = 420.2.

Example 137: (+/-) - (2- (aminomethyl) piperidine-1-yl) (2- (1-ethyl -1 H - indol-2-yl) -1-methyl -1 H -benzo[d]imidazol-5-yl)methanone

2-(1-Ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazole-5-carboxylic acid (110 mg, 0.344 mmol) in DMF (2 mL) HATU (157 mg, 0.413 mmol) was added to the stirred solution, followed by DIPEA (0.072 mL, 0.413 mmol). After stirring at rt for 30 min, (+/-)-(hexahydropyridin-2-ylmethyl)carbamic acid tert-butyl ester (81 mg, 0.379 mmol) was added and stirred at rt. 2h. The solvent was removed under reduced pressure and water (10 mL) was added to the residue. The cream white precipitate was filtered off and rinsed with water (2×5 mL). The precipitate was dried in a vacuum oven for 2 h to give 220 mg (113%) of cream solid (product of Boc protection). The Boc protected product was taken up in EtOAc (5 mL After stirring at rt for 30 min, the solvent was removed under reduced pressure and the dark purple residue was taken in MeOH to EtOAc (EtOAc). The column was washed with MeOH (3 CV) and eluted with methanol (2N) (3 CV). The ammonia fraction was combined and evaporated under reduced pressure. The residue (189 mg) was loaded onto a 10 g SNAP s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Appropriate fractions were combined and evaporated in vacuo to give (+)-(2-(aminomethyl)hexahydropyridin-1-yl) (2-(1-ethyl- 1H -indole) as a white solid. Indole-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone (11.4 mg, 0.027 mmol, 7.97% yield).

LCMS (Method B): Rt = 0.80 min, MH+ = 416.2.

Example 138a: ((3 S ,4 R )-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1- Single unknown mirror image isomer of methyl-1 H -benzo[d]imidazol-5-yl)methanone

Example 138b: ((3 S ,4 R )-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1 H -indol-2-yl)-1- Methyl-1 H -benzo[d]imidazol-5-yl)methanone, hydrochloride, single unknown mirror image isomer

To ((3 S ,4 R )-1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazole-5-carbonyl To a stirred solution of 4- fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester (45 mg, 0.087 mmol) in EtOAc (EtOAc) The resulting solution was stirred at rt for 3 h. The mixture was loaded onto a pre-equilibrated 2g SCX column and eluted with MeOH (3 CV), then the in MeOH 2M NH _{3 (3} CV) elution. The basic fractions were combined and the volatiles were removed under reduced pressure to afford ((3 S, 4 R) -3- amino-4-fluoro-piperidine-1-yl) (2- (1-ethyl - 1 H -Indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone (26.3 mg, 0.063 mmol, 72.4% yield).

LCMS (Method B): Rt = 0.78 min, MH+ = 420.2.

3 mg of free base was removed for analysis, and 1.0 M HCl in 1.1 equivalents of ether was added to the remaining material and dissolved in a minimum amount of DCM. The mixture was triturated with ether and dried under a stream of N _2, to give a yellow / white solid / powder ((3 S, 4 R) -3- amino-4-fluoro-piperidine-1-yl) (2- (1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (23.6 mg, 0.052 mmol, 59.8%) rate).

LCMS (Method B) Rt = 0.79, MH+ = 420.2

Example 139a: ((3 R ,4 S )-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-yl -1-1H-benzo[d]imidazol-5-yl)methanone single unknown mirror image isomer

Example 139b: ((3 R ,4 S )-3-Amino-4-fluorohexahydropyridin-1-yl)(2-(1-ethyl-1H-indol-2-yl)-1-yl -1H-benzo[d]imidazol-5-yl)methanone, hydrochloride, single unknown mirror image isomer

To ((3 R ,4 S )-1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazole- 5-carbonyl To a stirred solution of 4- fluorohexahydropyridin-3-yl)carbamic acid tert-butyl ester (36 mg, 0.069 mmol) in EtOAc (EtOAc) The resulting solution was stirred at rt for 3 h. The mixture was loaded onto a pre-equilibrated 2g SCX column and eluted with MeOH (3 CV), then the in MeOH 2M NH _{3 (3} CV) elution. The basic portion was combined and the volatiles were removed under reduced pressure to give ((3 R , 4S )-3-amino-4-fluorohexahydropyridin-1-yl) (2-(1-ethyl-) 1 H -Indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone (24 mg, 0.057 mmol, 83% yield).

LCMS (Method B): Rt = 0.779 min.

2.5 mg was removed for analysis and 1.0 M HCl in 1.1 equivalents of ether was added to the remaining material and dissolved in a minimum amount of DCM. The mixture was triturated with ether and dried under a stream of N ₂ and, to give a yellow / white solid / powder ((3 R, 4 S) -3- amino-4-fluoro-piperidine-1-yl) (2- (1-Ethyl-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (18.8 mg, 0.041 mmol, 59.5%) rate).

LCMS (Method B) Rt = 0.79, MH+ = 420.2

Example 140a: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone

Example 140b: ( R )-(3-Aminohexahydropyridin-1-yl)(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)- 1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride

To ( R )-(1-(2-(1-(cyclopropylmethyl)-6-methoxy-1H-indol-2-yl)-1-methyl-1 H -benzo[d] To a solution of the imidazole-5-carbonyl) hexahydropyridin-3-yl)carbamic acid tert-butyl ester (147 mg, 0.264 mmol) in EtOAc (EtOAc) The reaction was stirred at rt for 90 min. The volatiles were removed under reduced pressure to give a dark orange oil. The crude mixture was loaded onto a 5g SCX column pre-equilibrated and washed with MeOH (3 CV), then the in MeOH 2M NH _{3 (3} CV) elution. The basic portion was combined and the volatiles were removed under reduced pressure to give ( R )-(3-aminohexahydropyridin-1-yl)(2-(1-cyclopropylmethyl)- 6-Methoxy-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-yl)methanone (113 mg, 0.247 mmol, 94% yield).

LCMS (Method A): rt = 1.00 min.

5.0 mg was removed for analysis and 1.0 M HCl in 1.1 equivalents of ether was added to the remaining material and dissolved in a minimum amount of DCM. The mixture was triturated with ether and dried under a stream of N _2, to give a brown solid (R) - (3- amino-hexahydro-1-yl) (2- (1- (cyclopropylmethyl) -6 -Methoxy-1H-indol-2-yl)-1-methyl-1H-benzo[d]imidazol-5-yl)methanone, hydrochloride (110 mg, 0.223 mmol, 84% yield) .

LCMS (Method A) Rt = 1.00, MH+ = 458.3

Example 141: N -(3-Azabicyclo[4.1.0]heptan-1-yl)-2-(1-ethyl-1H-indol-2-yl)-1-methyl-1H-benzene And [d]imidazole-5-formamide

To 1-(2-(1-ethyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazol-5-carbamido)-3-aza Add 2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol) to a suspension of dicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (128 mg, 0.249 mmol) Stir overnight. The reaction mixture was then evaporated and redissolved in methanol then loaded onto a 10 g SCX-2 column and washed with methanol to remove TFA. The product was dissolved with 2M methanolic ammonia and then evaporated. The product was dissolved in 1:1 DMSO and methanol and purified by MDAP (Method B). The appropriate fractions were combined and loaded onto a 10 g SCX-2 column. Methanol was used to dissolve the formic acid and the product was dissolved with 2M methanol ammonia. The solvent was then evaporated. After standing under high vacuum for 4 h, a yellow viscous solid N- (3-azabicyclo[4.1.0]hept-1-yl)-2-(1-ethyl- 1H -indole-2- 1-methyl-1 H -benzo[d]imidazol-5-carboxamide (64 mg, 0.155 mmol, 62.1% yield).

LCMS (Method B): Rt = 0.83 min.

Example 142: (3-Aminohexahydropyridin-1-yl)(2-(1-benzyl-1 H -indol-2-yl)-1-methyl-1H-benzo[d]imidazole- 5-based) ketone

In a similar manner to Example 82 from (1-(2-(1-benzyl-1 H -indol-2-yl)-1-methyl-1 H -benzo[d]imidazole-5-carbonyl) Preparation of hexahydropyridin-3-yl)carbamic acid tert-butyl ester.

LCMS (Method B): Rt 0.91 min, MH ⁺ 464.3

Biological data PAD4 enzyme performance

Recombinant human PAD4 (residue 1-663) was shown to be an N-terminal GST-tagged fusion protein in E. coli. During protein purification, the GST tag was removed by cleavage with PreScission Protease (GE Healthcare). Enzymes were used in the FLINT NH ₃ release assay in the presence of Na-benzimidyl-L-arginine ethyl ester (BAEE) and the amount of NH3 released at known receptor/enzyme concentrations was measured. The activity of the final PAD4 enzyme and batch consistency were determined.

PAD4 enzyme analysis: Condition A

8 μl of PAD4 enzyme in assay buffer (a).: (100 mM HEPES, 50 mM NaCl, 2 mM DTT and 0.6 mg/ml BSA pH 8) or in assay buffer (b).: (100 mM HEPES, 50 mM NaCl, 2 mM) DTT, 7.5% glycerol and 1.5 mM CHAPS pH 8) were diluted to an analytical concentration of 75 nm and added to a well of Greiner high volume 384 well black plate containing 0.1 μl of different concentrations of compound or DMSO vehicle (final 0.8%) in. After pre-incubation at rt for 30 min, the reaction was initiated by the addition of 4 μl of a buffer containing 3 mM Na-benzylidene-L-arginine ethyl ester (BAEE), 100 mM HEPES, 50 mM NaCl, 600 uM CaCl ₂ (2H ₂ O) and 2 mM DTT, pH 8.0. After 100 min, the reaction was stopped by the addition of 38 μl of stop/detection buffer containing 50 mM EDTA, 2.6 mM phthalaldehyde and 2.6 mM DTT. The assay was incubated for 90 min at rt, after which the fluorescence signal (λ _ex 413 / λ _em 476) was measured on an Envision plate reader (Perkin Elmer Life Sciences, Waltham, MA, USA).

PAD4 Enzyme Analysis: Condition B

8 μl of PAD4 enzyme was diluted in assay buffer (100 mM HEPES, 50 mM NaCl, 2 mM DTT and 0.6 mg/ml BSA pH 8) to an assay concentration of 30 nM and added to a Greiner high volume 384 well black plate containing 0.1 μl of different Concentration of compound or DMSO vehicle (final 0.8%) in wells. After pre-incubation at rt for 30 min, the reaction was initiated by the addition of 4 μl of a buffer containing 3 mM Na-benzylidene-L-arginine ethyl ester (BAEE), 100 mM HEPES, 50 mM NaCl, 600 uM CaCl ₂ (2H ₂ O) and 2 mM DTT, pH 8.0. After 60 min, the reaction was stopped by the addition of 38 μl of stop/detection buffer containing 50 mM EDTA, 2.6 mM phthalaldehyde and 2.6 mM DTT. The assay was incubated for 90 min at rt, after which the fluorescence signal (λ _ex 405/λ _em 460) was measured on an Envision plate reader (Perkin Elmer Life Sciences, Waltham, MA, USA).

PAD2 enzyme performance

Recombinant human PAD2 (residue 1-665) was shown to be an N-terminal 6His-FLAG-tagged fusion protein in baculovirus-infected Sf9 insect cells. The activity of the final product was determined using a FLINT NH ₃ release assay.

PAD2 enzyme analysis

8 μl of PAD2 enzyme was diluted to an assay concentration of 30 nM in assay buffer (100 mM HEPES, 50 mM NaCl, 2 mM DTT, 7.5% glycerol, and 1.5 mM CHAPS pH 8) and added to the Greiner high volume 384 well black plate containing 0.1 Ll different concentrations of compound or DMSO vehicle (final 0.8%) in the wells. After pre-incubation at rt for 30 min, the reaction was initiated by the addition of 4 μl of a buffer containing 180 uM Na-benzylidene-L-arginine ethyl ester (BAEE), 100 mM HEPES, 50 mM NaCl, 240 uM CaCl ₂ (2H ₂ O) and 2 mM DTT, pH 8.0. After 90 min, the reaction was stopped by the addition of 38 μl of stop/detection buffer containing 50 mM EDTA, 2.6 mM phthalaldehyde and 2.6 mM DTT. The assay was incubated for 90 min at rt, after which the fluorescence signal (λ _ex 405/λ _em 460) was measured on an Envision plate reader (Perkin Elmer Life Sciences, Waltham, MA, USA).

The compounds of Examples 1a-142 were tested essentially as described above. Those skilled in the art will recognize that in vitro binding assays and cell-based assays for functional activity are subject to experimental variability. Therefore, it should be understood that the pIC ₅₀ values given below are merely exemplary.

result

Examples 1a-142 based on the above analysis, or similar analyzes PAD4 enzymes was tested and having a mean pIC ₅₀ values in the range of 5.1 to 7.4.

Examples 6,11a, 15,16,20b, 24,43,44,58a and analysis system 65 test assay or the like and having average pIC 6.4 to 7.4 in the range of ₅₀ values in the above PAD4 enzymes. Example 15 and analysis or the like in the above-described enzyme assay test PAD4 and having an average line 20b pIC ₅₀ value of 6.4. Examples 11a, 24 and 65 or the like based assay test analysis and having an average value of ₅₀ in the above-described pIC 6.8 PAD4 enzymes. Example 16 In the PAD4-based analysis or enzyme assay tests the like and having average pIC ₅₀ value of 6.9. Example 6 based on the above analysis, or similar analyzes PAD4 enzymes was tested and had an average pIC ₅₀ value of 7.0. In the above Examples 58a-based analysis or enzyme PAD4 similar analysis was tested and had an average pIC ₅₀ value of 7.1. Example 44 In the PAD4-based analysis or enzyme assay tests the like and having average pIC ₅₀ value of 7.3. Example 43 In the PAD4-based analysis or enzyme assay tests the like and having average pIC ₅₀ value of 7.4.

To evaluate the selectivity for PAD4 relative to PAD2, the following examples were tested in the above PAD2 enzyme assay or similar analysis - Examples 1a, 2, 12, 16, 18, 19, 20a, 20b, 22, 29, 32, 34, 37 , 43-45, 48, 51, 54, 58a, 58b, 59, 63, 65-68, 70, 74, 75, 95, 96, 111, 113, 114, 124 and 135- and having <4.1 to 5.0 The average pIC ₅₀ value in the range. The average pIC ₅₀ values for Examples 22, 29, 37, 51, 54, 63, 65, 67, 68, 70, 95, 96, 114, and 124 were all <4.1.

Claims (18)

a compound of formula (I), And a salt thereof; wherein: X is O or S; Y is N or CR ₂ R ₁ is -H or -C _1-6 alkyl; R ₂ is -H, -OH, -C _1-6 alkyl, - OC _1-6 alkyl, -CN, -halo, -C(=O)NH ₂ , -C _1-6 haloalkyl, -OC _1-6 alkyl-OC _1-6 alkyl, -OC _{1 -6-} alkyl-OH, -OC _1-6 alkyl-C(=O)NH ₂ , -OC _1-6 alkyl-CN, -OC _1-6 haloalkyl, -NH-C _1-6 alkane , -N(C _1-6 alkyl) ₂ or heteroaryl; R ₃ -C _1-6 alkyl, -C _1-6 alkyl-NH ₂ or -C _1-6 alkyl-OC _{1 -6} alkyl; R ₄ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-heteroaryl (wherein the heteroaryl is optionally used, 2 or 3 C _1-6 alkyl-substituted), -C _1-6 alkyl-phenyl (wherein the phenyl group is optionally substituted by 1, 2 or 3 substituents selected from the list consisting of : halo, C _1-6 alkyl and -OC _1-6 alkyl), -C _1-6 alkyl-heterocyclyl, -C _1-6 alkyl-C _3-6 cycloalkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-CN or -C _1-6 alkyl-OC _1-6 alkyl; R ₅ -H, -C _1-6 alkyl, -OC _{1 -6} alkyl, -OH, -halo or -CN; or R ₄ together with R ₅ is -(R ₄ )-CH ₂ CH ₂ O-(R ₅ )-, -(R ₄ )-CH ₂ CH ₂ CH ₂ O-(R ₅ )- or -(R ₄ )-CH(Me)CH ₂ O-(R ₅ )-, wherein -( R ₄ )- and -(R ₅ )- represent the position at which the alkenyloxy chain is attached to each ring atom; R ₆ is -H, -halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₇ is -H, -halo, -CN, -C _1-6 alkyl, -OC _1-6 alkyl or -OH; R ₈ -H, -F or -C _1-6 alkyl; R ₉ -H or -C _1-6 alkyl; and R ₁₀ is -H, and R ₁₁ is a 5- to 7-membered monocyclic saturated heterocyclic ring (containing 1 nitrogen atom and Case 1 oxygen atom) or 7-membered bicyclic heterocycle (containing 1 nitrogen atom) or -CH ₂ CH ₂ NH ₂ ; or NR ₁₀ R ₁₁ together form a 5- to 7-membered monocyclic or divalent group containing 1 nitrogen atom a ring-saturated or unsaturated heterocyclic ring wherein the heterocyclic ring is substituted by 1, 2 or 3 substituents independently selected from the list consisting of: -NH ₂ , -C _1-6 alkyl-NH ₂ ,- NH-C _1-6 alkyl, -NHC(=NH)CH ₂ Cl, -C _1-6 alkyl, -halo, -OC _1-6 alkyl, -OH and -C(O)NH ₂ . The compound of claim 1, or a salt thereof, wherein X is O. The compound of claim 1 or 2, or a salt thereof, wherein Y is CR ₂ . The compound of any one of claims 1 to 3, wherein R ₂ is -H, -O-Me, -O-CF ₃ , -CN, -Br, -CF ₃ ,-3-pyridyl, -C(=O)NH ₂ , -NMe ₂ , -NHMe, ethyl, methyl, -O-CH ₂ CH ₂ CH ₂ -OH, -O-Et, -O-CH ₂ CH ₂ -O-CH ₃ , -O-CH ₂ CH ₂ -OH, -OCH ₂ CN, -O-CH ₂ C(O)NH ₂ or -OH. The compound or a salt thereof according to any one of claims 1 to 4, wherein R ₃ is -methyl, -CH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ CH ₂ NH ₂ , -ethyl, -CH ₂ CH ₂ OCH ₃ or -isopropyl. The compound of any one of claims 1 to 5, wherein R ₄ is H, -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-heteroaryl, or a salt thereof (optionally substituted by 1 methyl group), -C _1-6 alkyl-phenyl (substituted by one or two substituents selected from the list consisting of: Cl, I, Me, and OMe), -C _1-6 alkyl-heterocyclyl, -C _1-6 alkyl-C _3-6 cycloalkyl, -C _1-6 alkyl-OH, -C _1-6 alkyl-CN or -C _1-6 alkyl-OC _1-6 alkyl. The compound of any one of claims 1 to 6 or a salt thereof, wherein -NR ₁₀ R ₁₁ is selected from the list consisting of hexahydropyridyl (as appropriate, one or two selected from the list consisting of Substituent substitution: -NH ₂ , -NH-C _1-6 alkyl, -C _1-6 alkyl-NH ₂ , -OC _1-6 alkyl, -OH, -C _1-6 alkyl, halo , -C(=O)NH ₂ and -NHC(=NH)CH ₂ Cl), dihydrohexahydropyridyl (optionally substituted by -NH ₂ ), azabicyclo[3.1.0]hexyl (as appropriate) Substituted by -NH ₂ ) and pyrrolidinyl (optionally substituted by one or two substituents selected from the list consisting of: -NH ₂ , -C _1-6 alkyl and -C _1-6 alkyl - NH ₂ ). A compound selected from the list consisting of Examples 1a to 142 or a salt thereof. A compound selected from the list consisting of: (3R)-1-[2-(1-benzyl-1H-indol-2-yl)-1-methyl-1H-1,3-benzoic acid (3R)-1-{1-methyl-2-[1-(pyridin-3-ylmethyl)-1H-inden-2-yl] -1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{1-methyl-2-[1-(2,2,2-trifluoro Ethyl)-1H-indol-2-yl]-1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{2-[1-( Cyclopropylmethyl)-1H-indol-2-yl]-1-methyl-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3R)-1 -(1-Methyl-2-{1-[(1-methyl-1H-pyrazol-4-yl)methyl]-1H-indol-2-yl}-1H-1,3-benzo (oxazol-5-carbonyl)hexahydropyridin-3-amine; (3R)-1-[2-(1-ethyl-1H-indol-2-yl)-7-methoxy-1-methyl -1H-1,3-benzobisazole-5-carbonyl]hexahydropyridin-3-amine; (3R)-1-{2-[1-(cyclopropylmethyl)-1H-indol-2-yl]-7-methoxy-1-methyl-1H-1,3-benzoic acid Zyrid-5-carbonyl}hexahydropyridin-3-amine; (3R)-1-{7-methoxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)- 1H-indol-2-yl]-1H-1,3-benzobisazole-5-carbonyl}hexahydropyridin-3-amine; (3S,4R)-3-amino-1-{7-A Oxy-1-methyl-2-[1-(2,2,2-trifluoroethyl)-1H-indol-2-yl]-1H-1,3-benzobisazole-5-carbonyl } hexahydropyridin-4-ol; and (3S,4R)-3-amino-1-{2-[1-(cyclopropylmethyl)-1H-indol-2-yl]-1-yl -1H-1,3-benzobisazol-5-carbonyl}hexahydropyridin-4-ol; and salts thereof. A compound of formula (I) according to any one of claims 1 to 9 for use as a pharmaceutically acceptable salt. A method of treating a condition mediated by PAD4 activity, comprising administering to a patient in need thereof a safe and effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9 . A method for treating rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus or psoriasis, the method comprising administering a therapeutically effective treatment to a patient in need thereof A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9 for use in therapy. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9 for use in the treatment of a condition mediated by PAD4 activity. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9 for use in the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcerative colitis, cancer, Cystic fibrosis, asthma, cutaneous lupus erythematosus or psoriasis. A use of a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition mediated by PAD4 activity. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of rheumatoid arthritis, vasculitis, systemic lupus erythematosus, ulcer Agent for colitis, cancer, cystic fibrosis, asthma, cutaneous lupus erythematosus or psoriasis. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.